Phosphonooxy quinazoline derivatives and their pharmaceutical use

ABSTRACT

Quinazoline derivatives of formula (I) wherein A is 5-membered heteroaryl containing a nitrogen atom and one or two further nitrogen atoms; compositions containing them, processes for their preparation and their use in therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a US National Stage under 35 U.S.C § 371 of International Application No. PCT/GB2003/005613 (filed Dec. 22, 2003) which claims priority under 35 U.S.C. § 119(a)-(d) to Application No. EP 02293238.8 filed on Dec. 24, 2002 and to Application No. EP 03291315.4 filed on Jun. 2, 2003.

The present invention relates to certain quinazoline derivatives for use in the treatment of certain diseases in particular to proliferative disease such as cancer and in the preparation of medicaments for use in the treatment of proliferative disease, to novel quinazoline compounds and to processes for their preparation, as well as pharmaceutical compositions containing them as active ingredient.

Cancer (and other hyperproliferative disease) is characterised by uncontrolled cellular proliferation. This loss of the normal regulation of cell proliferation often appears to occur as the result of genetic damage to cellular pathways that control progress through the cell cycle.

In eukaryotes, an ordered cascade of protein phosphorylation is thought to control the cell cycle. Several families of protein kinases that play critical roles in this cascade have now been identified. The activity of many of these kinases is increased in human tumours when compared to normal tissue. This can occur by either increased levels of expression of the protein (as a result of gene amplification for example), or by changes in expression of co activators or inhibitory proteins.

The first identified, and most widely studied of these cell cycle regulators have been the cyclin dependent kinases (or CDKs). Activity of specific CDKs at specific times is essential for both initiation and coordinated progress through the cell cycle. For example, the CDK4 protein appears to control entry into the cell cycle (the G0-G1-S transition) by phosphorylating the retinoblastoma gene product pRb. This stimulates the release of the transcription factor E2F from pRb, which then acts to increase the transcription of genes necessary for entry into S phase. The catalytic activity of CDK4 is stimulated by binding to a partner protein, Cyclin D. One of the first demonstrations of a direct link between cancer and the cell cycle was made with the observation that the Cyclin D1 gene was amplified and cyclin D protein levels increased (and hence the activity of CDK4 increased) in many human tumours (Reviewed in Sherr, 1996, Science 274: 1672-1677; Pines, 1995, Seminars in Cancer Biology 6: 63-72). Other studies (Loda et al., 1997, Nature Medicine 3(2): 231-234; Gemma et al., 1996, International Journal of Cancer 68(5): 605-11; Elledge et al. 1996, Trends in Cell Biology 6; 388-392) have shown that negative regulators of CDK function are frequently down regulated or deleted in human tumours again leading to inappropriate activation of these kinases.

More recently, protein kinases that are structurally distinct from the CDK family have been identified which play critical roles in regulating the cell cycle and which also appear to be important in oncogenesis. These include the newly identified human homologues of the Drosophila aurora and S. cerevisiae Ip11 proteins. The three human homologues of these genes Aurora-A, Aurora-B and Aurora-C (also known as aurora2, aurora1 and aurora3 respectively) encode cell cycle regulated serine-threonine protein kinases (summarised in Adams et al., 2001, Trends in Cell Biology. 11(2): 49-54). These show a peak of expression and kinase activity through G2 and mitosis. Several observations implicate the involvement of human aurora proteins in cancer. The Aurora-A gene maps to chromosome 20q13, a region that is frequently amplified in human tumours including both breast and colon tumours. Aurora-A may be the major target gene of this amplicon, since Aurora-A DNA is amplified and mRNA overexpressed in greater than 50% of primary human colorectal cancers. In these tumours Aurora-A protein levels appear greatly elevated compared to adjacent normal tissue. In addition, transfection of rodent fibroblasts with human Aurora-A leads to transformation, conferring the ability to grow in soft agar and form tumours in nude mice (Bischoff et al., 1998, The EMBO Journal. 17(11): 3052-3065). Other work (Zhou et al., 1998, Nature Genetics. 20(2): 189-93) has shown that artificial overexpression of Aurora-A leads to an increase in centrosome number and an increase in aneuploidy, a known event in the development of cancer. Further work has shown an increase in expression of Aurora-B (Adams et al., 2001, Chromsoma. 110(2):65-74) and Aurora-C (Kimura et al., 1999, Journal of Biological Chemistry, 274(11): 7334-40) in tumour cells when compared to normal cells.

Importantly, it has also been demonstrated that abrogation of Aurora-A expression and function by antisense oligonucleotide treatment of human tumour cell lines (WO 97/22702 and WO 99/37788) leads to cell cycle arrest and exerts an antiproliferative effect in these tumour cell lines. Additionally, small molecule inhibitors of Aurora-A and Aurora-B have been demonstrated to have an antiproliferative effect in human tumour cells (Keen et al. 2001, Poster #2455, American Association of Cancer research annual meeting), as has selective abrogation of Aurora-B expression alone by siRNA treatment (Ditchfield et al. 2003, journal of Cell Biology, 161(2): 267-280). This indicates that inhibition of the function of Aurora-A and/or Aurora-B will have an antiproliferative effect that may be useful in the treatment of human tumours and other hyperproliferative disease. Further, inhibition of Aurora kinases as a therapeutic approach to these diseases may have significant advantages over targeting signalling pathways upstream of the cell cycle (e.g. those activated by growth factor receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) or other receptors). Since the cell cycle is ultimately downstream of all of these diverse signalling events, cell cycle directed therapies such as inhibition of Aurora kinases would be predicted to be active across all proliferating tumour cells, whilst approaches directed at specific signalling molecules (e.g. EGFR) would be predicted to be active only in the subset of tumour cells which express those receptors. It is also believed that significant “cross talk” exists between these signalling pathways meaning that inhibition of one component may be compensated for by another.

A number of quinazoline derivatives have been proposed hitherto for use in the inhibition of various kinases. For example, WO 96/09294, WO 96/15118 and WO 99/06378 describe the use of certain quinazoline compounds as receptor tyrosine kinase inhibitors, which may be useful in the treatment of proliferative disease and WO 00/21955 discloses certain quinazoline derivatives as inhibitors of the effects of VEGF.

Quinazoline derivatives have also been disclosed for use in the inhibition of Aurora-A kinase. WO 02/00649 discloses quinazoline derivative bearing a 5-membered heteroaromatic ring where the ring is, in particular, substituted thiazole or substituted thiophene and co-pending patent application WO 03/055491 discloses quinazoline derivatives bearing an optionally substituted pyrazole ring. However despite the compounds of WO 02/00649 and WO 03/055491 there still exists the need for further compounds having Aurora kinase inhibitory properties.

The applicants have been successful in finding a novel series of compounds which inhibit the effects of the Aurora kinases and in particular Aurora-A and/or Aurora-B kinase and which have certain properties that make them particularly useful in formulating medicaments for the treatment of disease. In particular the compounds are of use in the treatment of proliferative disease such as cancer occurring as either solid and haematological tumours where Aurora kinases are known to be active, and especially in diseases such as colorectal, breast, lung, prostate, pancreatic or bladder and renal cancer as well as leukaemias and lymphomas.

According to one aspect of the present invention there is provided a compound of formula (I):

wherein A is 5-membered heteroaryl containing a nitrogen atom and optionally containing one or two further nitrogen atoms;

-   X is O, S, S(O), S(O)₂ or NR¹⁴; -   m is 0, 1, 2 or 3; -   Z is a group selected from —NR¹R², phosphonooxy, C₃₋₆cycloalkyl     which C₃₋₆cycloalkyl is substituted by phosphonooxy or C₁₋₄alkyl     substituted by phosphonooxy, and a 4- to 7-membered ring linked via     a carbon atom containing a nitrogen atom and optionally containing a     further nitrogen atom, which ring may be saturated, partially     saturated or unsaturated wherein the ring is substituted on carbon     or nitrogen by phosphonooxy or C₁₋₄alkyl substituted by     phosphonooxy, and wherein the ring is optionally further substituted     on carbon or nitrogen by 1, 2 or 3 halo or C₁₋₄alkyl groups; -   R¹ is a group selected from —COR⁸, —CONR⁸R⁹ and C₁₋₆alkyl which     C₁₋₆alkyl is substituted by phosphonooxy and optionally further     substituted by 1 or 2 halo or methoxy groups; -   R² is a group selected from hydrogen, —COR¹⁰, —CONR¹⁰R¹¹ and     C₁₋₆alkyl which C₁₋₆alkyl is optionally substituted by 1, 2 or 3     halo or C₁₋₄alkoxy groups, —S(O)_(p)R¹¹ (where p is 0, 1 or 2) or     phosphonooxy, or R² is a group selected from C₂₋₆alkenyl,     C₂₋₆alkynyl, C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₄alkyl; -   or R¹ and R² together with the nitrogen to which they are attached     form a 4- to 7-membered ring optionally containing a further     nitrogen atom which ring may be saturated, unsaturated or partially     saturated, wherein the ring is substituted on carbon or nitrogen by     a group selected from phosphonooxy and C₁₋₄alkyl which C₁₋₄alkyl is     substituted by phosphonooxy or —NR⁸R⁹, and where the ring is     optionally further substituted on carbon or nitrogen by 1, 2 or 3     halo or C₁₋₄alkyl groups; -   R³ is a group selected from hydrogen, halo, cyano, nitro,     C₁₋₆alkoxy, C₁₋₆alkyl, —OR¹², —CHR¹²R¹³, —OC(O)R¹², —C(O)R¹²,     —NR¹²C(O)R¹³, —C(O)NR¹²R¹³, —NR¹²SO₂R¹³ and —NR¹²R¹³; -   R⁴ is hydrogen or a group selected from C₁₋₄alkyl, heteroaryl,     heteroarylC₁₋₄alkyl, aryl and arylC₁₋₄alkyl which group is     optionally substituted by 1, 2 or 3 substitutents selected from     halo, methyl, ethyl, cyclopropyl and ethynyl; -   R⁵ is selected from hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,     C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₄alkyl; -   R⁶ and R⁷ are independently selected from hydrogen, halo, C₁₋₄alkyl,     C₃₋₆cycloalkyl, hydroxy and C₁₋₄alkoxy; -   R⁸ is C₁₋₄alkyl substituted by phosphonooxy and optionally further     substituted by 1 or 2 halo or methoxy groups; -   R⁹ is selected from hydrogen and C₁₋₄alkyl; -   R¹⁰ is selected from hydrogen and C₁₋₄alkyl optionally substituted     by halo, C₁₋₄alkoxy, S(O)_(q) (where q is 0, 1 or 2) or phosphonoxy; -   R¹¹, R¹², R¹³ and R¹⁴ are independently selected from hydrogen,     C₁₋₄alkyl and heterocyclyl; or a pharmaceutically acceptable salt     thereof.

Within the present invention, it is to be understood that, insofar as certain compounds of formula (I) herein defined may exist in optically active or racemic forms by virtue of one or more asymmetric carbon or sulphur atoms, the invention includes in its definition any such optically active or racemic form which possesses Aurora kinase inhibitory activity and in particular Aurora-A and/or Aurora-B kinase inhibitory activity. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.

Within the present invention it is to be understood that a compound of formula (I) or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which has Aurora kinase inhibitory activity and in particular Aurora-A and/or Aurora-B kinase inhibitory activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.

It is also to be understood that certain compounds of formula (I) and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which have Aurora kinase inhibitory activity and in particular Aurora-A and/or Aurora-B kinase inhibitory activity.

The present invention relates to the compounds of formula (I) as herein defined as well as to the salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (I) and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of compounds of formula (I) as herein defined which are sufficiently basic to form such salts. Such acid addition salts include but are not limited to furmarate, methanesulphonate, hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulphuric acid. In addition where compounds of formula (I) are sufficiently acidic, salts are base salts and examples include but are not limited to, an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salt for example triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine or amino acids such as lysine.

The compounds of formula (I) may also be provided as in vivo hydrolysable esters. An in vivo hydrolysable ester of a compound of formula (I) containing carboxy or hydroxy group is, for example a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid or alcohol. Such esters can be identified by administering, for example, intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluid.

Suitable pharmaceutically acceptable esters for carboxy include C₁₋₆alkoxymethyl esters for example methoxymethyl, C₁₋₆alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example 1-cyclohexylcarbonyloxyethyl, 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl, and C₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in the compounds of this invention.

Suitable pharmaceutically acceptable esters for hydroxy include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include C₁₋₁₀alkanoyl, for example formyl, acetyl, benzoyl, phenylacetyl, substituted benzoyl and phenylacetyl; C₁₋₁₀alkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; di-C₁₋₄alkylcarbamoyl and N-(di-C₁₋₄alkylaminoethyl)-N-C₁₋₄alkylcarbamoyl (to give carbamates); di-C₁₋₄alkylaminoacetyl and carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, C₁₋₄alkylaminomethyl and di-(C₁₋₄alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4-position of the benzoyl ring. Other interesting in vivo hydrolysable esters include, for example, R^(A)C(O)OC₁₋₆alkyl-CO—, wherein R^(A) is for example, benzyloxy-C₁₋₄alkyl, or phenyl. Suitable substituents on a phenyl group in such esters include, for example, 4-C₁₋₄piperazino-C₁₋₄alkyl, piperazino-C₁₋₄alkyl and morpholino-C₁₋₄alkyl.

In this specification the generic term “alkyl” includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched-chain alkyl groups such as “tert-butyl” are specific for the branched chain version only. An analogous convention applies to other generic terms, for example “alkenyl” and “alkynyl”.

“Cycloalkyl” is a monocyclic, saturated alkyl ring and “aryl” is a monocyclic or bicyclic aromatic ring.

Unless otherwise specified “heteroaryl” is a monocyclic or bicyclic aromatic ring containing 5 to 10 ring atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen where a ring nitrogen or sulphur may be oxidised.

“Heterocyclyl” is a saturated, unsaturated or partially saturated monocyclic or bicyclic ring containing 4 to 12 atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen, which ring may be carbon or nitrogen linked, wherein a —CH₂— group can optionally be replaced by a —C(O)—; wherein a ring nitrogen or sulphur atom is optionally oxidised to form the N-oxide or S-oxide(s); wherein a ring —NH is optionally substituted by acetyl, formyl, methyl or mesyl; and wherein a ring is optionally substituted by one or more halo.

“Phosphonooxy” is in one aspect a group of formula —OP(O)(OH)₂. However the term “phosphonooxy” also includes salts of this group such as those formed with alkali metal ions such as sodium or potassium ions or alkaline earth metal ions, for example calcium or magnesium ions.

Where optional substituents are chosen from “1 or 2”, from “1,2, or 3” or from “1, 2, 3 or 4” groups or substituents it is to be understood that this definition includes all substituents being chosen from one of the specified groups i.e. all substitutents being the same or the substituents being chosen from two or more of the specified groups i.e. the substitutents not being the same.

Compounds of the present invention have been named with the aid of computer software (ACD/Name version 6.6 or ACD Name Batch version 6.0).

Suitable values for any R group (R¹ to R¹⁴) or any part or substitutent for such groups include:

-   for C₁₋₄alkyl: methyl, ethyl, propyl, isopropyl, butyl,     2-methylpropyl and tert-butyl; -   for C₁₋₆alkyl: C₁₋₄alkyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl     and hexyl; -   for C₂₋₄alkenyl: vinyl, allyl and 1-propenyl; -   for C₂₋₆alkenyl: C₂₋₄alkenyl, 1-butenyl, 2-butenyl, 3-butenyl,     2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and     4-hexenyl; -   for C₂₋₄alkynyl: ethynyl, 1-propynyl, 2-propynyl and 3-butynyl; -   for C₂₋₆alkynyl: C₂₋₄alkynyl, 2-pentynyl, hexynyl and     1-methylpent-2-ynyl; -   for C₃₋₆cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and     cyclohexyl; -   for C₃₋₆cycloalkylC₁₋₄alkyl: cyclopropylmethyl, cyclopropylethyl,     cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl; -   for aryl: phenyl and naphthyl; -   for arylC₁₋₄alkyl: benzyl, phenethyl, naphthylmethyl and     naphthylethyl; -   for halo: fluoro, chloro, bromo and iodo; -   for C₁₋₄alkoxy: methoxy, ethoxy, propoxy and isopropoxy; -   for C₁₋₆alkoxy: C₁₋₄alkoxy, pentyloxy, 1-ethylpropoxy and hexyloxy; -   for heteroaryl: pyridyl, imidazolyl, quinolinyl, cinnolyl,     pyrimidinyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, triazolyl,     oxazolyl, isoxazolyl and pyrazinyl and preferably thiazolyl,     pyridyl, imidazolyl and pyrimidinyl; -   for heteroarylC₁₋₄alkyl: pyridylmethyl, pyridylethyl,     pyrimidinylethyl, pyrimidinylpropyl, pyrimidinylbutyl,     imidazolylpropyl, imidazolylbutyl, quinolinylpropyl,     1,3,4-triazolylpropyl and oxazolylmethyl; -   for heterocyclyl: furyl, thienyl, pyrrolyl, pyrrolidinyl,     imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl,     pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,     quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl,     benzoxazolyl, benzothienyl, benzofuryl, piperidinyl,     N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl,     N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl,     oxetanyl, morpholinyl, tetrahydroisoquinolinyl,     tetrahydroquinolinyl, indolinyl, pyranyl, dihydro-2H-pyranyl,     tetrahydrofuranyl, 2,5-dioximidazolidinyl,     2,2-dimethyl-1,3-dioxolanyl and 3,4-dimethylenedioxybenzyl.

It should be noted that examples given for terms used in the description are not limiting.

Preferred values of A, X, m, Z, R³, R⁴, R⁵, R⁶ and R⁷ are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined herein.

In one aspect of the invention A is pyrrolyl, pyrazolyl, imidazolyl or triazolyl. In a further aspect A is a group of formula (a), (b), (c), (d) or (e):

where * is the point of attachment to the X group of formula (I) and ** is the point of attachment to the (CR⁶R⁷) group of formula (I). In a preferred aspect A is pyrazolyl. In a more preferred aspect A is a group of formula (a) as defined above.

In one aspect of the invention X is NR¹⁴, O or S. In another aspect X is NR¹⁴. In yet another aspect X is NH.

In one aspect of the invention m is 1, 2 or 3. In one aspect m is 1 or 2. In another aspect m is 0, 2 or 3. In another aspect m is 0, 1 or 2. In yet another aspect m is 1. In a further aspect m is 2.

In one aspect of the invention Z is —NR¹R² or a 5- to 6-membered saturated ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring is substituted on carbon or nitrogen by phosphonooxy or C₁₋₄alkyl substituted by phosphonooxy. In another aspect Z is —NR¹R².

In one aspect of the invention R¹ is C₁₋₅alkyl substituted by phosphonooxy. In another aspect R¹ is C₁₋₅alkyl substituted by phosphonooxy and further substituted by 1 or 2 halo. In a further aspect R¹ is 2-phosphonooxyethyl, 2-phosphonooxy-1,1-dimethylethyl, 2-phosphonooxy-2-methylethyl, 3-phosphonooxy-1,1-dimethylpropyl, 3-phosphonooxypropyl and 4-phosphonooxybutyl. In yet another aspect R¹ is 2-phosphonooxyethyl, 2-phosphonooxy-1,1-dimethylethyl, 3-phosphonooxy-1,1-dimethylpropyl or 3-phosphonooxypropyl. In yet another aspect R¹ is 2-phosphonooxyethyl.

In one aspect of the invention R² is selected from hydrogen and C₁₋₆alkyl which C₁₋₆alkyl is optionally substituted by 1, 2 or 3 halo or C₁₋₄alkoxy groups, or R² is selected from C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₄alkyl. In another aspect R² is hydrogen, allyl, 2-propynyl, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, butyl, 2,2-dimethylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, 3,3,3-trifluoropropyl or 2-methoxyethyl.

In one aspect of the invention R¹ and R² together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C₁₋₄alkyl which C₁₋₄alkyl is substituted by phosphonooxy or —NR⁸R⁹, and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 C₁₋₄alkyl groups. In another aspect of the invention R¹ and R² together with the nitrogen to which they are attached form a piperidine, pyrrolidine or piperazine ring which is substituted by a group selected from phosphonooxy, phosphonooxymethyl, 2-phosphonooxyethyl, N-ethyl-N-(2-phosphonooxyethyl)aminomethyl and N-(2-phosphonooxyethyl)aminomethyl and where the ring is optionally further substituted by 1 or 2 methyl. In a further aspect of the invention R¹ and R² together with the nitrogen to which they are attached form 4-(phosphonooxymethyl)piperidinyl, 2-(phosphonooxymethyl)pyrrolidinyl, 4-(2-phosphonooxyethyl)piperazinyl, 3-(phosphonooxy)pyrrolidinyl, 3-(phosphonooxy)piperidinyl, 2-[N-ethyl-N-(2-phosphonooxyethyl)aminomethyl]pyrrolidinyl, 4-(phosphonooxy)piperidinyl, 2-[N-(2-phosphonooxyethyl)aminomethyl]pyrrolidinyl, 4-(2-phosphonooxyethyl)piperidinyl, 2-(2-phosphonooxyethyl)pyrrolidinyl and 2-(2-phosphonooxyethyl)piperidinyl. In yet another aspect R¹ and R² together with the nitrogen to which they are attached form 4-(phosphonooxymethyl)piperidinyl, 2-(phosphonooxymethyl)pyrrolidinyl, 2-(2-phosphonooxyethyl)pyrrolidinyl and 3-(phosphonooxy)piperidinyl. In a further aspect R¹ and R² together with the nitrogen to which they are attached form 2-(phosphonooxymethyl)pyrrolidinyl.

In one aspect of the invention R³ is C₁₋₄alkoxy, halo or hydrogen. In a further aspect R³ is C₁₋₄alkoxy or hydrogen. In another aspect R³ is methoxy. In another aspect R³ is hydrogen. In yet a further aspect R³ is fluoro.

In one aspect R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro. In another aspect R⁴ is 3-fluorophenyl, 3-chlorophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 2-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl and 2,5-difluorophenyl. In a further aspect R⁴ is 3-fluorophenyl, 3,5-difluorophenyl and 2,3-difluorophenyl. In one aspect R⁴ is 3-fluorophenyl. In a further aspect R⁴ is 3,5-difluorophenyl. In yet another aspect R⁴ is 2,3-difluorophenyl.

In one aspect of the invention R⁵ is hydrogen or methyl. In another aspect R⁵ is hydrogen.

In one aspect of the invention R⁶ is hydrogen, fluoro, chloro or methyl. In another aspect R⁶ is hydrogen.

In one aspect of the invention R⁷ is hydrogen, fluoro, chloro or methyl. In another aspect R⁷ is hydrogen.

In one aspect R⁸ is 2-phosphonooxyethyl.

In one aspect of the invention R⁹ is hydrogen, methyl or ethyl.

In one aspect of the invention R¹⁰ is hydrogen, methyl or ethyl.

In one aspect of the invention R¹¹ is hydrogen, methyl or ethyl.

In one aspect of the invention R¹² is hydrogen or methyl.

In one aspect of the invention R¹³ is hydrogen or methyl.

In one aspect of the invention R¹⁴ is hydrogen or methyl.

A preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a), (b), (c), (d) or (e) as defined above; -   X is NH; -   m is 0, 1, 2 or 3; -   Z is —NR¹R² or a 5- to 6-membered saturated ring linked via a carbon     atom containing a nitrogen atom and optionally containing a further     nitrogen atom, which ring is substituted on carbon or nitrogen by     phosphonooxy or C₁₋₄alkyl substituted by phosphonooxy; -   R¹ is C₁₋₅alkyl substituted by phosphonooxy; -   R² is selected from hydrogen and C₁₋₆alkyl which C₁₋₆alkyl is     optionally substituted by 1, 2 or 3 halo or C₁₋₄alkoxy groups or R²     is selected from C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl and     C₃₋₆cycloalkylC₁₋₄alkyl; -   or R¹ and R² together with the nitrogen to which they are attached     form a saturated 5- to 6-membered ring optionally containing a     further nitrogen atom wherein the ring is substituted on carbon or     nitrogen by a group selected from phosphonooxy and C₁₋₄alkyl which     C₁₋₄alkyl is substituted by phosphonooxy or —NR⁸R⁹, and where the     ring is optionally further substituted on carbon or nitrogen by 1 or     2 C₁₋₄alkyl groups; -   R³ is C₁₋₄alkoxy, halo or hydrogen; -   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro; -   R⁵ is hydrogen or methyl; and -   R^(6 and R) ⁷ are independently hydrogen, fluoro, chloro or methyl; -   or a pharmaceutically acceptable salt thereof.

A preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a), (b), (c), (d) or (e) as defined above; -   X is NH; -   m is 1, 2 or 3; -   Z is —NR¹R²; -   R¹ is C₁₋₅alkyl substituted by phosphonooxy; -   R² is selected from hydrogen and C₁₋₆alkyl which C₁₋₆alkyl is     optionally substituted by 1, 2 or 3 halo or C₁₋₄alkoxy groups, or R²     is selected from C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl and     C₃₋₆cycloalkylC₁₋₄alkyl; -   R³ is C₁₋₄alkoxy, halo or hydrogen; -   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro; -   R⁵ is hydrogen or methyl; and -   R⁶ and R⁷ are independently hydrogen, fluoro, chloro or methyl;     or a pharmaceutically acceptable salt thereof.

Another preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a) as defined above; -   X is NH; -   m is 1, 2 or 3; -   Z is —NR¹R²; -   R¹ is C₁₋₅alkyl substituted by phosphonooxy; -   R² is selected from hydrogen and C₁₋₆alkyl which C₁₋₆alkyl is     optionally substituted by 1, 2 or 3 halo or C₁₋₄alkoxy groups, or R²     is selected from C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl and     C₃₋₆cycloalkylC₁₋₄alkyl; -   R³ is C₁₋₄alkoxy, halo or hydrogen; -   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro; -   R⁵ is hydrogen; and -   R⁶ and R⁷ are each hydrogen;     or a pharmaceutically acceptable salt thereof.

Yet another preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a) as defined above; -   X is NH; -   m is 1 or 2; -   Z is —NR¹R²; -   R¹ is C₁₋₅alkyl substituted by phosphonooxy; -   R² is selected from hydrogen and C₁₋₆alkyl which C₁₋₆alkyl is     optionally substituted by 1, 2 or 3 halo or C₁₋₄alkoxy groups, or R²     is selected from C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl and     C₃₋₆cycloalkylC₁₋₄alkyl; -   R³ is C₁₋₄alkoxy; -   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro; -   R⁵ is hydrogen; and -   R⁶ and R⁷ are each hydrogen;     or a pharmaceutically acceptable salt thereof.

A further preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a) as defined above; -   X is NH; -   m is 1, 2 or 3; -   Z is —NR¹R²; -   R¹ is C₁₋₅alkyl substituted by phosphonooxy; -   R² is selected from hydrogen and C₁₋₆alkyl which C₁₋₆alkyl is     optionally substituted by 1, 2 or 3 halo or C₁₋₄alkoxy groups, or R²     is selected from C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl and     C₃₋₆cycloalkylC₁₋₄alkyl; -   R³ is hydrogen; -   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro; -   R⁵ is hydrogen; and -   R⁶ and R⁷ are each hydrogen;     or a pharmaceutically acceptable salt thereof.

A further preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a) as defined above; -   X is NH; -   m is 1 or 2; -   Z is —NR¹R²; -   R¹ is C₁₋₅alkyl substituted by phosphonooxy; -   R² is selected from hydrogen and C₁₋₆alkyl which C₁₋₆alkyl is     optionally substituted by 1, 2 or 3 halo or C₁₋₄alkoxy groups, or R²     is selected from C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl and     C₃₋₆cycloalkylC₁₋₄alkyl; -   R³ is fluoro; -   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro; -   R⁵ is hydrogen; and -   R⁶ and R⁷ are each hydrogen;     or a pharmaceutically acceptable salt thereof.

Another preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a), (b), (c), (d) or (e) as defined above; -   X is NH; -   m is 0, 1 or 2; -   Z is —NR¹R² -   R¹ and R² together with the nitrogen to which they are attached form     a saturated 5- to 6-membered ring optionally containing a further     nitrogen atom which ring is substituted by a group selected from     phosphonooxy and C₁₋₄alkyl which C₁₋₄alkyl is substituted by     phosphonooxy or —NR⁸R⁹, and where the ring is optionally further     substituted by 1 or 2 C₁₋₄alkyl groups; -   R³ is C₁₋₄alkoxy, halo or hydrogen; -   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro; -   R⁵ is hydrogen or methyl; and -   R⁶ and R⁷ are independently hydrogen, fluoro, chloro or methyl; -   R⁸ is 2-phosphonooxyethyl; and -   R⁹ is hydrogen, methyl or ethyl;     or a pharmaceutically acceptable salt thereof.

A further preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a) as defined above; -   X is NH; -   m is 0, 1 or 2; -   Z is —NR¹R² -   R¹ and R² together with the nitrogen to which they are attached form     a saturated 5- to 6-membered ring optionally containing a further     nitrogen atom wherein the ring is substituted on carbon or nitrogen     by a group selected from phosphonooxy and C₁₋₄alkyl which C₁₋₄alkyl     is substituted by phosphonooxy or —NR⁸R⁹, and where the ring is     optionally further substituted on carbon or nitrogen by 1 or 2     C₁₋₄alkyl groups; -   R³ is C, alkoxy, halo or hydrogen; -   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro; -   R⁵ is hydrogen or methyl; and -   R⁶ and R⁷ are independently hydrogen, fluoro, chloro or methyl; -   R⁸ is 2-phosphonooxyethyl; and -   R⁹ is hydrogen, methyl or ethyl;     or a pharmaceutically acceptable salt thereof.

A further preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a) as defined above; -   X is NH; -   m is 0, 1 or 2; -   Z is —NR¹R² -   R¹ and R² together with the nitrogen to which they are attached form     a saturated 5- to 6-membered ring optionally containing a further     nitrogen atom wherein the ring is substituted on carbon or nitrogen     by a group selected from phosphonooxy and C₁₋₄alkyl which C₁₋₄alkyl     is substituted by phosphonooxy or —NR⁸R⁹, and where the ring is     optionally further substituted on carbon or nitrogen by 1 or 2     C₁₋₄alkyl groups; -   R³ is C₁₋₄alkoxy; -   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro; -   R⁵ is hydrogen; and -   R⁶ and R⁷ are each hydrogen; -   R⁸ is 2-phosphonooxyethyl; and -   R⁹ is hydrogen, methyl or ethyl;     or a pharmaceutically acceptable salt thereof.

A further preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a) as defined above; -   X is NH; -   m is 0, 1 or 2; -   Z is —NR¹R² -   R¹ and R² together with the nitrogen to which they are attached form     a saturated 5- to 6-membered ring optionally containing a further     nitrogen atom wherein the ring is substituted on carbon or nitrogen     by a group selected from phosphonooxy and C₁₋₄alkyl which C₁₋₄alkyl     is substituted by phosphonooxy or —NR⁸R⁹, and where the ring is     optionally further substituted on carbon or nitrogen by 1 or 2     C₁₋₄alkyl groups; -   R³ is hydrogen; -   R⁴ is phenyl optionally substituted by 1 or 2 of fluoro or chloro; -   R⁵ is hydrogen; and -   R⁶ and R⁷ are each hydrogen; -   R⁸ is 2-phosphonooxyethyl; and -   R⁹ is hydrogen, methyl or ethyl;     or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, a preferred compound of the invention is any compound selected from:

-   {1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-4-yl}methyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl     dihydrogen phosphate; -   {(2S)-1-[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl-}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   {(2R)-1-[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   {(2S)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6     methoxyquinazolin-7-yl}oxy)propyl](propyl)amino]ethyl dihydrogen     phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl     dihydrogen phosphate; -   2-{(2,2-dimethylpropyl)[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-3-yl     dihydrogen phosphate; -   {(2R)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](prop-2-yn-1-yl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isopropyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](prop-2-yn-1-yl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl)     (2-methoxyethyl)amino]ethyl dihydrogen phosphate; -   2-{[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{(cyclobutylmethyl)[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](3,3,3-trifluoropropyl)amino]ethyl     dihydrogen phosphate; -   2-{allyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{cyclobutyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{cyclopentyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{(cyclopropyl)[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{(cyclopropylmethyl)[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate and -   2-{cyclobutyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate;     or a pharmaceutically acceptable salt thereof.

A more preferred compound of the invention is any compound selected from:

-   2-{4-[({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](isopropyl)amino]ethyl     dihydrogen phosphate; -   3-{[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}-3-methylbutyl     dihydrogen phosphate; -   2-{(2S)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}ethyl     dihydrogen phosphate; -   {(2R)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](butyl)amino]ethyl     dihydrogen phosphate; -   2-{cyclopentyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   {(2S)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   {(2S)-1-[3-({4-[(5     {2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-{cyclopentyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl     dihydrogen phosphate; -   2-{[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}-2-methylpropyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     dihydrogen phosphate; -   {(2R)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   3-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]propyl     dihydrogen phosphate     2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl](2-methoxyethyl)amino]ethyl     dihydrogen phosphate -   2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl](propyl)amino]ethyl     dihydrogen phosphate; -   2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl](ethyl)amino]ethyl     dihydrogen phosphate; -   {(2R)-1-[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)butyl](methyl)amino]ethyl     dihydrogen phosphate; and -   {(2S)-1-[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate;     or a pharmaceutically acceptable salt thereof

A further preferred compound is:

-   2-{ethyl[3-({6-fluoro-4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate;     or a pharmaceutically acceptable salt thereof.

A more preferred compound is any compound selected from:

-   {1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-4-yl}methyl     dihydrogen phosphate; -   {(2S)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl     dihydrogen phosphate; -   2-{(2,2-dimethylpropyl)[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-3-yl     dihydrogen phosphate; -   2-{[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](3,3,3-trifluoropropyl)amino]ethyl     dihydrogen phosphate; -   2-{cyclopropyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{cyclobutyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   {(2S)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-{cyclopentyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl     dihydrogen phosphate; -   2-{[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}-2-methylpropyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     dihydrogen phosphate; -   {(2R)-1     [3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   3-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]propyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl](2-methoxyethyl)amino]ethyl     dihydrogen phosphate; and -   2-{ethyl[3-({6-fluoro-4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate;     or a pharmaceutically acceptable salt thereof

A further preferred compound is any compound selected from:

-   {1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-4-yl}methyl     dihydrogen phosphate; -   {(2S)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl     dihydrogen phosphate; -   2-{(2,2-dimethylpropyl)[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-3-yl     dihydrogen phosphate; -   2-{[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](3,3,3-trifluoropropyl)amino]ethyl     dihydrogen phosphate; -   2-{cyclopropyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; and -   2-{cyclobutyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate;     or a pharmaceutically acceptable salt thereof.

Another preferred compound is any compound selected from:

-   2-[[3-({4[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl     dihydrogen phosphate; -   2-{(2,2-dimethylpropyl)[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](3,3,3-trifluoropropyl)amino]ethyl     dihydrogen phosphate; -   2-{cyclopropyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino)     ethyl dihydrogen phosphate; and -   2-{cyclobutyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate;     or a pharmaceutically acceptable salt thereof.

A particularly preferred compound is any compound selected from:

-   {(2S)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-{cyclopentyl[3′-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl     dihydrogen phosphate; -   2-{[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}-2-methylpropyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     dihydrogen phosphate; -   {(2R)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   3-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]propyl     dihydrogen phosphate; and -   2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl)-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl](2-methoxyethyl)amino]ethyl     dihydrogen phosphate;     or a pharmaceutically acceptable salt thereof.

An especially preferred compound of the invention is any compound selected from:

-   2-{cyclopentyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-[[3-({4[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl     dihydrogen phosphate; -   2-{[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}-2-methylpropyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     dihydrogen phosphate; -   3-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]propyl     dihydrogen phosphate; and -   2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl](2-methoxyethyl)amino]ethyl     dihydrogen phosphate;     or a pharmaceutically acceptable salt thereof.

A further preferred compound is any compound selected from:

-   2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl     dihydrogen phosphate; -   {(2S)-1-[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   {(2R)-1-[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     dihydrogen phosphate; and -   2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](prop-2-yn-1-yl)amino]ethyl     dihydrogen phosphate;     or a pharmaceutically acceptable salt thereof.

A further preferred compound is any compound selected from:

-   2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     dihydrogen phosphate; and -   2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](prop-2-yn-1-yl)amino]ethyl     dihydrogen phosphate;     or a pharmaceutically acceptable salt thereof.

Another more preferred compound is any compound selected from:

-   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl     dihydrogen phosphate; -   {(2R)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isopropyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](prop-2-yn-1-yl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](2-methoxyethyl)amino]ethyl     dihydrogen phosphate; -   2-{(cyclobutylmethyl)[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{allyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{cyclobutyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{cyclopentyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{(cyclopropylmethyl)[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{4-[({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyl     dihydrogen phosphate; -   2-[[3-(f{4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](isopropyl)amino]ethyl     dihydrogen phosphate; -   3-{[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}-3-methylbutyl     dihydrogenphosphate; -   2-{(2S)-1-[3-({4[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}ethyl     dihydrogen phosphate; -   {(2R)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](butyl)amino]ethyl     dihydrogen phosphate; -   2-{cyclopentyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   {(2S)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl](propyl)amino]ethyl     dihydrogen phosphate; -   2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl](ethyl)amino]ethyl     dihydrogen phosphate; -   {(2R)-1-[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)butyl](methyl)amino]ethyl     dihydrogen phosphate; and -   {(2S)1-[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate;     or a pharmaceutically acceptable salt thereof.

A particularly preferred compound is any compound selected from:

-   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl     dihydrogen phosphate; -   {(2R)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isopropyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](prop-2-yn-1-yl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](2-methoxyethyl)amino]ethyl     dihydrogen phosphate; -   2-{(cyclobutylmethyl)[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{allyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{cyclobutyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{cyclopentyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; and -   2-{(cyclopropylmethyl)[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate;     or a pharmaceutically acceptable salt thereof.

Yet another preferred compound is any compound selected from:

-   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isopropyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](prop-2-yn-1-yl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](2-methoxyethyl)amino]ethyl     dihydrogen phosphate; -   2-{(cyclobutylmethyl)[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{allyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{cyclobutyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-{cyclopentyl[3-({-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; and -   2-{(cyclopropylmethyl)[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate;     or a pharmaceutically acceptable salt thereof.

Another preferred compound is any compound selected from:

-   2-{4-[({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](isopropyl)amino]ethyl     dihydrogen phosphate; -   3-{[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}-3-methylbutyl     dihydrogen phosphate; -   2-f{(2S)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}ethyl     dihydrogen phosphate; -   {(2R)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](butyl)amino]ethyl     dihydrogen phosphate; -   2-{cyclopentyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   {(2S)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl](propyl)amino]ethyl     dihydrogen phosphate; -   2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl](ethyl)amino]ethyl     dihydrogen phosphate; -   {(2R)-1-[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)butyl](methyl)amino]ethyl     dihydrogen phosphate; and

{(2S)-1-[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl]pyrrolidin-2-yl}methyl dihydrogen phosphate;

or a pharmaceutically acceptable salt thereof.

Yet another preferred compound is any compound selected from:

-   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](isopropyl)amino]ethyl     dihydrogen phosphate; -   3-{[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}-3-methylbutyl     dihydrogen phosphate; -   2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     dihydrogen phosphate; -   2-[[3-({-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](butyl)amino]ethyl     dihydrogen phosphate; -   2-{cyclopentyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]amino}ethyl     dihydrogen phosphate; -   2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl](propyl)amino]ethyl     dihydrogen phosphate; -   2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-20     quinazolin-7-yl}oxy)butyl](ethyl)amino]ethyl dihydrogen phosphate;     and -   2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)butyl](methyl)amino]ethyl     dihydrogen phosphate;     or a pharmaceutically acceptable salt thereof.

A further particularly preferred compound is any compound selected from:

-   {1-[3-(f{4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-4-yl}methyl     dihydrogen phosphate; -   {(2S)-1-[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   {(2R)-1-[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogenphosphate; -   {(2S)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-3-yl     dihydrogen phosphate; -   {(2R)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   2-{(2S)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}ethyl     dihydrogen phosphate; -   {(2R)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   {(2S)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   {(2S)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   {(2R)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; -   {(2R)-1-[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate; and -   {(2S)-1-[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl]pyrrolidin-2-yl}methyl     dihydrogen phosphate;     or a pharmaceutically acceptable salt thereof.

A further embodiment of the invention comprises any one of:

-   N-(2,3-difluorophenyl)-2-{3-[(7-{[1-(2-hydroxyethyl)piperidin-4-yl]methoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(3-hydroxy-1,1-dimethylpropyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(2-hydroxyethyl)pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(butyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide; -   N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(3-fluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide; -   N-(3-fluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxy-1,1-dimethylethyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(3-fluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(2,3-difluorophenyl)-2-{3-[(7-{4-[(2-hydroxyethyl)(propyl)amino]butoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(3-fluorophenyl)-2-{3-[(7-{4-[ethyl(2-hydroxyethyl)amino]butoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(2,3-difluorophenyl)-2-{3-[(7-{4-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]butoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(2,3-difluorophenyl)-2-{3-[(7-{4-[(2-hydroxyethyl)(methyl)amino]butoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(2,3-difluorophenyl)-2-{3-[(7-{4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]butoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   2-{3-[(7-{3-[ethyl(3-hydroxypropyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide; -   N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(2-methoxyethyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;     and -   2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6-fluoroquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide;     or a pharmaceutically acceptable salt thereof.

Synthetic routes to any of compounds can be found in the examples.

A preferred compound of this embodiment is any compound selected from:

-   N-(3-fluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide; -   N-(3-fluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxy-1,1-dimethylethyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(3-fluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(3-fluorophenyl)-2-{3-[(7-{4-[ethyl(2-hydroxyethyl)amino]butoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   2-{3-[(7-{3-[ethyl(3-hydroxypropyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide; -   N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(2-methoxyethyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;     and -   2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6-fluoroquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide;     or a pharmaceutically acceptable salt thereof.

Another preferred compound is any compound selected from:

-   N-(2,3-difluorophenyl)-2-{3-[(7-{[1-(2-hydroxyethyl)piperidin-4-yl]methoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(3-hydroxy-1,1-dimethylpropyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(2-hydroxyethyl)pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(butyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide; -   N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(25)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(2,3-difluorophenyl)-2-{3-[(7-{4-[(2-hydroxyethyl)(propyl)amino]butoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(2,3-difluorophenyl)-2-{3-[(7-{4-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]butoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide; -   N-(2,3-difluorophenyl)-2-{3-[(7-{4-[(2-hydroxyethyl)(methyl)amino]butoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;     and -   N-(2,3-difluorophenyl)-2-{3-[(7-{4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]butoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide;     or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises converting a compound of formula (II) into a compound of formula (I by phosphorylation of an appropriate hydroxy group:

where A, X, m, R³, R⁴, R⁵, R⁶, R⁷ and R⁹ are as defined for formula (I); and Z′ is a group selected from —NR^(1′)R^(2′), hydroxy, C₃₋₆cycloalkyl which C₃₋₆cycloalkyl is substituted by hydroxy or C₁₋₄alkyl substituted by hydroxy, and a 4- to 7-membered ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring may be saturated, unsaturated or partially saturated wherein the ring is substituted on carbon or nitrogen by hydroxy or C₁₋₄alkyl substituted by hydroxy and wherein the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo or C₁₋₄alkyl groups; R^(1′) is a group selected from —COR^(8′), —CONR^(8′)R⁹ and C₁₋₆alkyl which C₁₋₆alkyl is substituted by hydroxy and optionally further substituted by 1 or 2 halo or methoxy groups; R^(2′) is a group selected from hydrogen, —COR ¹⁰, —CONR¹⁰R¹¹ and C₁₋₆alkyl which C₁₋₆alkyl is optionally substituted by 1, 2 or 3 halo or C₁₋₄alkoxy groups or —S(O)_(p)R¹¹ (where p is 0, 1 or 2) or hydroxy, or R² is selected from C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₄alkyl; or R^(1′) and R^(2′) together with the nitrogen to which they are attached form a 4- to 7-membered ring optionally containing a further nitrogen atom which may be saturated, unsaturated or partially saturated wherein the ring is substituted on carbon or nitrogen by a group selected from hydroxy and C₁₋₄alkyl substituted by hydroxy or —NR^(8′)R⁹ and where the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo or C₁₋₄alkyl groups; and where R^(8′) is C₁₋₄alkyl substituted by hydroxy and optionally further substituted by 1 or 2 halo or methoxy groups: and thereafter if necessary:

-   i) converting a compound of the formula (I) into another compound of     the formula (I); and/or -   ii) removing any protecting groups; and/or -   iii) forming a pharmaceutically acceptable salt thereof.

Phosphorylation may be suitably performed by treatment with 1-H tetrazole (or a suitable replacement such as S-ethyl tetrazole or pyridinium hydrochloride) and di-tert-butyldiethylphosphoramidite or dibenzyldiethylphosphoramidite at 5 to 35° C. under an inert atmosphere for 30 minutes to 4 hours followed by treatment with an oxidizing agent such as meta-chloroperbenzoic acid (mCPBA) or 30% aqueous hydrogen peroxide at −10 to 25° C. for 2 to 18 hours. Deprotection of the tert-butyl groups to yield the phosphate group is required as a final step with these reagents and may be readily achieved by treatment with 4.0 N hydrochloric acid in 1,4-dioxane at 10 to 35° C. for 12 to 18 hours.

This process may further comprise a method for the preparation of a compound of formula (II) where Z′ is —NR^(1′)R^(2′) which method comprises the reaction of a compound of formula (III) where L is a leaving group such as halo (e.g. chloro):

with an amine of formula (IV):

Suitable reaction conditions for this method include heating a compound of formula (III) with an excess of amine of formula (IV) in an inert solvent such as dimethylacetamide, with or without the addition of a suitable catalyst (such as tetra-n-butylammoniuim iodide or potassium iodide) at a temperature of 50 to 100° C. for 12 to 72 hours. In an alternative procedure, the leaving group L in formula (III) may be a carboxaldehyde and the reaction with amine (IV) may be carried out under reductive conditions using a reducing agent such as sodium cyanoborohydride.

The amines of formula (IV) are known in the art or may be prepared by the skilled person using methods known in the art.

The process may further comprise a method for the preparation of a compound of formula (III) where X is NR¹⁴ which method comprises the reaction of a compound of formula (V) where R′ and R″ are alkyl groups such as methyl and ethyl and L is as defined in relation to formula (III):

with a compound of formula (VI) where R may be either hydrogen or a group such as tert-butoxycarbonyl (Boc) or trityl:

Such a reaction can be achieved under a range of conditions described in the literature, such as heating a compound of formula (V) with a compound of formula (VI) in a solvent such as acetic acid at a temperature of 100 to 130° C. for 2 to 18 hours.

Alternatively, the process may further comprise a method for the preparation of a compound of formula (III) where X is NR¹⁴, O or S which method comprises the reaction of a compound of formula (VII) where R* is a leaving group such as halo (e.g. chloro):

with a compound of formula (VI) where R is either hydrogen or tert-butoxycarbonyl (Boc) or trityl. Such a reaction can be achieved under a range of conditions described in the literature, such as heating a compound of formula (VII) with a compound of formula (VI) in a solvent such as isopropanol or dimethylacetamide, in the presence of an acid catalyst such as hydrochloric acid, at a temperature of 80 to 100° C. for 2 to 6 hours. Alternatively the reaction may be effected using a base such as sodium hydride carrying out the reaction in an inert solvent such as dimethylformamide at a temperature of 50 to 80° C. for 2 to 6 hours.

Compounds of formula (V) can be prepared from a compound of formula (VIII) where P is a hydroxy protecting group such as benzyl:

by reaction with a compound of formula (IX) where L′ is a leaving group such as halo (e.g. bromo) and L is as defined in relation to formula (III):

Such a reaction can be achieved (after removal of the protecting group using a method selected from those already described in the literature) under a range of conditions described in the literature such as heating a compound of formula (VIII) with a compound of formula (IX) in the presence of a catalyst such as caesium carbonate in a solvent such as acetonitrile at a temperature of 80 to 100° C. for 1 to 4 hours.

A method for the preparation of a compound of formula (VIII) comprises the reaction of a compound of formula (X) where P is as defined in relation for formula (VIII):

with an appropriate acetal such as N,N-dimethylformamide dimethyl acetal. The reaction is suitably effected in an organic solvent such as toluene or benzene, at elevated temperature, conveniently at the reflux temperature of the solvent.

Compounds of formula (X) are either known compounds or they can be prepared by the skilled person using conventional methods. In particular, compounds of formula (X) may be prepared by reduction of the corresponding nitro compound of formula (XI) where P is as described in relation to formula (VIII):

Suitable reaction conditions are illustrated hereinafter.

Compounds of formula (XI) may be obtained by nitration of a compound of formula (XII) where P is as defined in relation to formula (VIII)

for example, using nitric acid as the nitrating agent. Again, suitable reaction conditions are illustrated hereinafter.

The nitrile of formula (XII) may be derived by reaction of the corresponding aldehyde of formula (XIII) with hydroxylamine as illustrated hereinafter:

The process may further comprise a method for the preparation of a compound according to formula (VII) which method comprises the reaction of a compound of formula (XIV)

where L* is a hydroxy group, with a suitable chlorinating agent such as thionyl chloride, phoshoryl chloride or phoshorus pentachloride. Again, suitable reaction conditions are illustrated hereinafter.

Compounds of formula (XIV) are either known compounds or they can be prepared by the skilled person using conventional methods. In particular, compounds of formula (XIV) may be prepared by reaction of a compound of formula (XV) where L″ is a leaving group such as halo (fluoro)

with a compound of formula (XVI) where L* is a hydroxy group:

Suitable reaction conditions are illustrated hereinafter.

Compounds of formula (XV) are either known compounds or they can be prepared by the skilled person using conventional methods. In particular, compounds of formula (XV) may be prepared by reaction of a compound of formula (XVII) (where L″ is a leaving group such as halo (fluoro) and L′″ is an alkoxy or hydroxy group) by reaction with neat formamide at a temperature of 140 to 200° C. for 3 to 6 hours.

Suitable reaction conditions are illustrated hereinafter.

Compounds of formula (XVII) are either known compounds or they can be prepared by the skilled person using conventional methods. In particular, compounds of formula (XVII) may be prepared by reduction of a compound of formula (XVIII) (where L″ is a leaving group such as halo (fluoro) and L′″ is an alkoxy or hydroxy group) using a reducing agent such as sodium dithionite in a water: dichloromethane solvent system at ambient temperature for 1 to 3 hours.

Compounds of formula (XVIII) may be obtained by nitration of a compound of formula (XIX) where L″ and L′″ are as defined in relation to formula (XVIII)

for example, using nitric acid as the nitrating agent. Again, suitable reaction conditions are illustrated hereinafter.

The process may further comprise a method for the preparation of a compound according to formula (VI) where X is NR¹⁴, O or S which method comprises the reaction of a compound of formula (XX), where P is a suitable protecting group:

with an amine of formula HNR⁴R⁵ in the presence of a coupling reagent (such as O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) and diisopropylethylamine in a solvent (such as dimethylacetamide) under inert and anhydrous conditions.

A compound of formula (XX) where X is NR¹⁴ and P is COOR may be prepared from a compound of formula (XXI):

with a compound of formula (XXII) where L is an appropriate leaving group:

Suitable reagent and reaction conditions for this reaction include the use of di(tert-butyl)dicarbonate and triethylamine in tetrahydrofuran at 0° C. under a nitrogen atmosphere.

A compound of formula (III) may also be prepared (following deprotection) from a compound of formula (XX) by reacting it with a compound of formula (V) under a range of conditions described in the literature, such as heating the reaction mixture in a solvent such as acetic acid at a temperature of 100 to 130° C. for 2 to 18 hours. The product, a compound of formula (XXIII):

may then be reacted with an amine of formula HNR⁴R⁵ in the presence of a coupling agent (such as O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) and diisopropylethylamine in a solvent (such as dimethylacetamide) under inert and anhydrous conditions.

Further a compound of formula (XXIII) may also be prepared by reacting a deprotected compound of formula (XX) with a compound of formula (VII) under a range of conditions described in the literature, such as heating the reaction mixture in a solvent such as isopropanol or dimethylacetamide, in the presence of an acid catalyst such as hydrochloric acid, at a temperature of 80 to 100° C. for 2 to 6 hours. Alternatively the reaction may be effected using a base such as sodium hydride; carrying out the reaction in an inert solvent such as dimethylformamide at a temperature of 50 to 80° C. for 2 to 6 hours.

Compounds of formula (XXI) which comprise a heteraromatic ring are made according to the literature. However for illustrative purpose, when A is a pyrazole ring, a compound of formula (XXI) may be prepared according to the following scheme:

It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogen group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.

It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in association with a pharmaceutically acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal track, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.

Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, soya bean oil, coconut oil, or preferably olive oil, or any other acceptable vehicle.

Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible or lyophilised powders and granules suitable for preparation of an aqueous suspension or solution by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, solutions, emulsions or particular systems, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in polyethylene glycol.

Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art.

Compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30 μm or much less preferably 5 μm or less and more preferably between 5 μm and 1 μm, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose. The powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50 mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.

For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

Therefore in a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy. Further provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament. A compound of formula (I), or a pharmaceutically acceptable salt thereof, is also provided for use in the treatment of a disease where the inhibition of one or more Aurora kinase is beneficial. In particular it is envisaged that inhibition of Aurora-A kinase and/or Aurora-B kinase may be beneficial. Preferably inhibition of Aurora-B kinase is beneficial. A compound of formula (I), or a pharmaceutically acceptable salt thereof, has further use in the treatment of hyperproliferative diseases such as cancer and in particular colorectal, breast, lung, prostate, pancreatic or bladder and renal cancer or leukemias or lymphomas.

Additionally a compound of formula (I), or a pharmaceutically acceptable salt thereof is provided for use in a method of treatment of a warm-blooded animal such as man by therapy. According to this aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the method of treating a human suffering from a disease in which the inhibition of one or more Aurora kinases is beneficial, comprising the steps of administering to a person in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In particular it is envisaged that inhibition of Aurora-A kinase and/or Aurora-B kinase may be beneficial. Preferably inhibition of Aurora-B kinase is beneficial. Further provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the method of treating a human suffering from a hyperproliferative disease such as cancer and in particular particular colorectal, breast, lung, prostate, pancreatic or bladder and renal cancer or leukemias or lymphomas, comprising the steps of administering to a person in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a disease where the inhibition of one or more Aurora kinase is beneficial. In particular it is envisaged that inhibition of Aurora-A kinase and/or Aurora-B kinase may be beneficial. Preferably inhibition of Aurora-B kinase is beneficial. In another aspect of the invention, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of hyperproliferative diseases such as cancer and in particular colorectal, breast, lung, prostate, pancreatic or bladder and renal cancer or leukemias or lymphomas.

For the above mentioned therapeutic uses the dose administered will vary with the compound employed, the mode of administration, the treatment desired, the disorder indicated and the age and sex of the animal or patient. The size of the dose would thus be calculated according to well known principles of medicine.

In using a compound of formula (I) for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.05 mg/kg to 50 mg/kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will be used.

The treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:—

-   (i) antiproliferative/antineoplastic drugs and combinations thereof,     as used in medical oncology, such as alkylating agents (for example     cis-platin, carboplatin, cyclophosphamide, nitrogen mustard,     melphalan, chlorambucil, busulphan and nitrosoureas);     antimetabolites (for example antifolates such as fluoropyrimidines     like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine     arabinoside and hydroxyurea; antitumour antibiotics (for example     anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,     epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);     antimitotic agents (for example vinca alkaloids like vincristine,     vinblastine, vindesine and vinorelbine and taxoids like taxol and     taxotere); and topoisomerase inhibitors (for example     epipodophyllotoxins like etoposide and teniposide, amsacrine,     topotecan and camptothecin); -   (ii) cytostatic agents such as antioestrogens (for example     tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene),     antiandrogens (for example bicalutamide, flutamide, nilutamide and     cyproterone acetate), LHRH antagonists or LHRH agonists (for example     goserelin, leuprorelin and buserelin), progestogens (for example     megestrol acetate), aromatase inhibitors (for example as     anastrozole, letrozole, vorazole and exemestane) and inhibitors of     5α-reductase such as finasteride; -   (iii) agents which inhibit cancer cell invasion (for example     metalloproteinase inhibitors like marimastat and inhibitors of     urokinase plasminogen activator receptor function); -   (iv) inhibitors of growth factor function, for example such     inhibitors include growth factor antibodies, growth factor receptor     antibodies (for example the anti-erbb2 antibody trastuzumab     [Herceptin™] and the anti-erbb1 antibody cetuximab [C225]), farnesyl     transferase inhibitors, tyrosine kinase inhibitors and     serine-threonine kinase inhibitors, for example inhibitors of the     epidermal growth factor family (for example EGFR family tyrosine     kinase inhibitors such as     N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine     (gefitinib, AZD1839),     N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine     (erlotinib, OSI-774) and     6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine     (CI 1033)), for example inhibitors of the platelet-derived growth     factor family and for example inhibitors of the hepatocyte growth     factor family; -   (v) antiangiogenic agents such as those which inhibit the effects of     vascular endothelial growth factor, (for example the anti-vascular     endothelial cell growth factor antibody bevacizumab [Avastin™],     compounds such as those disclosed in International Patent     Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354)     and compounds that work by other mechanisms (for example linomide,     inhibitors of integrin αvβ3 function and angiostatin); -   (vi) vascular damaging agents such as Combretastatin A4 and     compounds disclosed in International Patent Applications WO     99/02166, WO00/40529, WO 00/41669, WO01/92224, WO02/04434 and     WO02/08213; -   (vii) antisense therapies, for example those which are directed to     the targets listed above, such as ISIS 2503, an anti-ras antisense; -   (viii) gene therapy approaches, including for example approaches to     replace aberrant genes such as aberrant p53 or aberrant BRCA1 or     BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such     as those using cytosine deaminase, thymidine kinase or a bacterial     nitroreductase enzyme and approaches to increase patient tolerance     to chemotherapy or radiotherapy such as multi-drug resistance gene     therapy; and -   (ix) immunotherapy approaches, including for example ex vivo and in     vivo approaches to increase the immunogenicity of patient tumour     cells, such as transfection with cytokines such as interleukin 2,     interleukin 4 or granulocyte-macrophage colony stimulating factor,     approaches to decrease T-cell anergy, approaches using transfected     immune cells such as cytokine-transfected dendritic cells,     approaches using cytokine-transfected tumour cell lines and     approaches using anti-idiotypic antibodies.

In addition a compound of the invention may be used in combination with one or more cell cycle inhibitors. In particular with cell cycle inhibitors which inhibit bub1, bubR1 or CDK. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically active agent within its approved dosage range.

In addition to their use in therapeutic medicine, the compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of cell cycle activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

In the above other pharmaceutical composition, process, method, use and medicament manufacture features, the alternative and preferred embodiments of the compounds of the invention described herein also apply.

The compounds of the invention inhibit the serine-threonine kinase activity of the Aurora kinases, in particular Aurora-A and/or Aurora-B and thus inhibit the cell cycle and cell proliferation. These properties may be assessed for example, using one or more of the procedures set out below. Whilst not wishing to be bound by theoretical constraints, it is believed that the compounds of formula (I) described herein may act as prodrugs. In procedures (c) and (d) set out below it is believed that a phosphonooxy group present in the compound of formula (I) is cleaved in situ to yield a hydroxy group and that such cleavage is necessary for activity is these assays.

(a) In Vitro Aurora-A Kinase Inhibition Test

This assay determines the ability of a test compound to inhibit serine-threonine kinase activity. DNA encoding Aurora-A may be obtained by total gene synthesis or by cloning. This DNA may then be expressed in a suitable expression system to obtain polypeptide with serine-threonine kinase activity. In the case of Aurora-A, the coding sequence was isolated from cDNA by polymerase chain reaction (PCR) and cloned into the BamH1 and Not1 restriction endonuclease sites of the baculovirus expression vector pFastBac HTc (GibcoBRL/Life technologies). The 5′ PCR primer contained a recognition sequence for the restriction endonuclease BamH1 5′ to the Aurora-A coding sequence. This allowed the insertion of the Aurora-A gene in frame with the 6 histidine residues, spacer region and rTEV protease cleavage site encoded by the pFastBac HTc vector. The 3′ PCR primer replaced the Aurora-A stop codon with additional coding sequence followed by a stop codon and a recognition sequence for the restriction endonuclease Not1. This additional coding sequence (5′ TAC CCA TAC GAT GTT CCA GAT TAC GCT TCT TAA 3′) encoded for the polypeptide sequence YPYDVPDYAS. This sequence, derived from the influenza hemagglutin protein, is frequently used as a tag epitope sequence that can be identified using specific monoclonal antibodies. The recombinant pFastBac vector therefore encoded for an N-terminally 6 his tagged, C terminally influenza hemagglutin epitope tagged Aurora-A protein. Details of the methods for the assembly of recombinant DNA molecules can be found in standard texts, for example Sambrook et al. 1989, Molecular Cloning—A Laboratory Manual, 2^(nd) Edition, Cold Spring Harbor Laboratory press and Ausubel et al. 1999, Current Protocols in Molecular Biology, John Wiley and Sons Inc.

Production of recombinant virus can be performed following manufacturer's protocol from GibcoBRL. Briefly, the pFastBac-1 vector carrying the Aurora-A gene was transformed into E. coli DH10Bac cells containing the baculovirus genome (bacmid DNA) and via a transposition event in the cells, a region of the pFastBac vector containing gentamycin resistance gene and the Aurora-A gene including the baculovirus polyhedrin promoter was transposed directly into the bacmid DNA. By selection on gentamycin, kanamycin, tetracycline and X-gal, resultant white colonies should contain recombinant bacmid DNA encoding Aurora-A. Bacmid DNA was extracted from a small scale culture of several BH10Bac white colonies and transfected into Spodoptera frugiperda Sf21 cells grown in TC100 medium (GibcoBRL) containing 10% serum using CellFECTIN reagent (GibcoBRL) following manufacturer's instructions. Virus particles were harvested by collecting cell culture medium 72 hrs post transfection. 0.5 mls of medium was used to infect 100 ml suspension culture of Sf21s containing 1×10⁷ cells/ml. Cell culture medium was harvested 48 hrs post infection and virus titre determined using a standard plaque assay procedure. Virus stocks were used to infect Sf9 and “High 5” cells at a multiplicity of infection (MOI) of 3 to ascertain expression of recombinant Aurora-A protein.

For the large scale expression of Aurora-A kinase activity, Sf21 insect cells were grown at 28° C. in TC100 medium supplemented with 10% foetal calf serum (Viralex) and 0.2% F68 Pluronic (Sigma) on a Wheaton roller rig at 3 r.p.m. When the cell density reached 1.2×10⁶ cells ml⁻¹ they were infected with plaque-pure Aurora-A recombinant virus at a multiplicity of infection of 1 and harvested 48 hours later. All subsequent purification steps were performed at 4° C. Frozen insect cell pellets containing a total of 2.0×10⁸ cells were thawed and diluted with lysis buffer (25 mM HEPES (N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulphonic acid]) pH7.4 at 4° C., 100 mM KCl, 25 mM NaF, 1 mM Na₃VO₄, 1 mM PMSF (phenylmethylsulphonyl fluoride), 2 mM 2-mercaptoethanol, 2 mM imidazole, 1 μg/ml aprotinin, 1 μg/ml pepstatin, 1 μg/ml leupeptin), using 1.0 ml per 3×10⁷ cells. Lysis was achieved using a dounce homogeniser, following which the lysate was centrifuged at 41,000 g for 35 minutes. Aspirated supernatant was pumped onto a 5 mm diameter chromatography column containing 500 μl Ni NTA (nitrilo-tri-acetic acid) agarose (Qiagen, product no. 30250) which had been equilibrated in lysis buffer. A baseline level of UV absorbance for the eluent was reached after washing the column with 12 ml of lysis buffer followed by 7 ml of wash buffer (25 mM HEPES pH7.4 at 4° C., 100 mM KCl, 20 mM imidazole, 2 mM 2-mercaptoethanol). Bound Aurora-A protein was eluted from the column using elution buffer (25 mM HEPES pH7.4 at 4° C., 100 mM KCl, 400 mM imidazole, 2 mM 2-mercaptoethanol). An elution fraction (2.5 ml) corresponding to the peak in WV absorbance was collected. The elution fraction, containing active Aurora-A kinase, was dialysed exhaustively against dialysis buffer (25 mM HEPES pH7.4 at 4° C., 45% glycerol (v/v), 100 mM KCl, 0.25% Nonidet P40 (v/v), 1 mM dithiothreitol).

Each new batch of Aurora-A enzyme was titrated in the assay by dilution with enzyme diluent (25 mM Tris-HCl pH7.5, 12.5 mM KCl, 0.6 mM DTT). For a typical batch, stock enzyme is diluted 1 in 666 with enzyme diluent and 20 μl of dilute enzyme is used for each assay well. Test compounds (at 10 mM in dimethylsulphoxide (DMSO) were diluted with water and 10 μof diluted compound was transferred to wells in the assay plates. “Total” and “blank” control wells contained 2.5% DMSO instead of compound. Twenty microliters of freshly diluted enzyme was added to all wells, apart from “blank” wells. Twenty microliters of enzyme diluent was added to “blank” wells. Twenty microliters of reaction mix (25 mM Tris-HCl, 78.4 mM KCl, 2.5 mM NaF, 0.6 mM dithiothreitol, 6.25 mM MnCl₂, 6.25 mM ATP, 7.5 μM peptide substrate [biotin-LRRWSLGLRRWSLGLRRWSLGLRRWSLG]) containing 0.2 μCi [γ³³P]ATP (Amersham Pharmacia, specific activity≧2500 Ci/mmol) was then added to all test wells to start the reaction. The plates were incubated at room temperature for 60 minutes. To stop the reaction 100 μl 20% v/v orthophosphoric acid was added to all wells. The peptide substrate was captured on positively-charged nitrocellulose P30 filtermat (Whatman) using a 96-well plate harvester (TomTek) and then assayed for incorporation of ³³P with a Beta plate counter. “Blank” (no enzyme) and “total” (no compound) control values were used to determine the dilution range of test compound which gave 50% inhibition of enzyme activity.

In this test, the compounds of the invention give 50% inhibition of enzyme activity at concentrations of 0.3 nM to 1000 nM and in particular compound 5 in Table 1 gave 50% inhibition of enzyme activity at a concentration of 5.5 nM.

(b) In Vitro Aurora-B Kinase Inhibition Test

This assay determines the ability of a test compound to inhibit serine-threonine kinase activity. DNA encoding Aurora-B may be obtained by total gene synthesis or by cloning. This DNA may then be expressed in a suitable expression system to obtain polypeptide with serine-threonine kinase activity. In the case of Aurora-B, the coding sequence was isolated from cDNA by polymerase chain reaction (PCR) and cloned into the pFastBac system in a manner similar to that described above for Aurora-A (i.e. to direct expression of a 6-histidine tagged Aurora-B protein).

For the large scale expression of Aurora-B kinase activity, Sf21 insect cells were grown at 28° C. in TC100 medium supplemented with 10% foetal calf serum (Viralex) and 0.2% F68 Pluronic (Sigma) on a Wheaton roller rig at 3 r.p.m. When the cell density reached 1.2×10⁶ cells ml⁻¹ they were infected with plaque-pure Aurora-B recombinant virus at a multiplicity of infection of 1 and harvested 48 hours later. All subsequent purification steps were performed at 4° C. Frozen insect cell pellets containing a total of 2.0×10⁸ cells were thawed and diluted with lysis buffer (50 mM HEPES (N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulphonic acid]) pH7.5 at 4° C., 1 mM Na₃VO₄, 1 mM PMSF (phenylmethylsulphonyl fluoride), 1 mM dithiothreitol, 1 μg/ml aprotinin, 1 μg/ml pepstatin, 1 μg/ml leupeptin), using 1.0 ml per 2×10⁷ cells. Lysis was achieved using a sonication homogeniser, following which the lysate was centrifuged at 41,000 g for 35 minutes. Aspirated supernatant was pumped onto a 5 mm diameter chromatography column containing 1.0 ml CM sepharose Fast Flow (Amersham Pharmacia Biotech) which had been equilibrated in lysis buffer. A baseline level of UV absorbance for the eluent was reached after washing the column with 12 ml of lysis buffer followed by 7 ml of wash buffer (50 mM HEPES pH7.4 at 4° C., 1 mM dithiothreitol). Bound Aurora-B B protein was eluted from the column using a gradient of elution buffer (50 mM HEPES pH7.4 at 4° C., 0.6 M NaCl, 1 mM dithiothreitol, running from 0% elution buffer to 100% elution buffer over 15 minutes at a flowrate of 0.5 ml/min). Elution fractions (1.0 ml) corresponding to the peak in UV absorbance was collected. Elution fractions were dialysed exhaustively against dialysis buffer (25 mM HEPES pH7.4 at 4° C., 45% glycerol (v/v), 100 mM KCl, 0.05% (v/v) IGEPAL CA630 (Sigma Aldrich), 1 mM dithiothreitol). Dialysed fractions were assayed for Aurora-B kinase activity.

Each new batch of Aurora-B enzyme was titrated in the assay by dilution with enzyme diluent (25 mM Tris-HCl pH7.5, 12.5 mM KCl, 0.6 mM DTT). For a typical batch, stock enzyme is diluted 1 in 40 with enzyme diluent and 20 μl of dilute enzyme is used for each assay well. Test compounds (at 10 mM in dimethylsulphoxide (DMSO) were diluted with water and 10 μl of diluted compound was transferred to wells in the assay plates. “Total” and “blank” control wells contained 2.5% DMSO instead of compound. Twenty microliters of freshly diluted enzyme was added to all wells, apart from “blank” wells. Twenty microliters of enzyme diluent was added to “blank” wells. Twenty microliters of reaction mix (25 mM Tris-HCl, 78.4 mM KCl, 2.5 mM NaF, 0.6 mM dithiothreitol, 6.25 mM MnCl₂, 37.5 mM ATP, 25 μM peptide substrate [biotin-LRRWSLGLRRWSLGLRRWSLGLRRWSLG]) containing 0.2 μCi [γ³³P]ATP (Amersham Pharmacia, specific activity≧2500 Ci/mmol) was then added to all test wells to start the reaction. The plates were incubated at room temperature for 60 minutes. To stop the reaction 100 μl 20% v/v orthophosphoric acid was added to all wells. The peptide substrate was captured on positively-charged nitrocellulose P30 filtermat (Whatman) using a 96-well plate harvester (TomTek) and then assayed for incorporation of ³³P with a Beta plate counter. “Blank” (no enzyme) and “total” (no compound) control values were used to determine the dilution range of test compound which gave 50% inhibition of enzyme activity.

In this test, the compounds of the invention give 50% inhibition of enzyme activity at concentrations of 0.3 nM to 1000 nM and in particular compound 5 in Table 1 gave 50% inhibition of enzyme activity at a concentration of 1.6 nM.

(c) In Vitro Cell Proliferation Assay

This and other assays can be used to determine the ability of a test compound to inhibit the growth of adherent mammalian cell lines, for example the human tumour cell line SW620 (ATCC CCL-227). This assay determines the ability of at test compound to inhibit the incorporation of the thymidine analogue, 5′-bromo-2′-deoxy-uridine (BrdU) into cellular DNA. SW620 or other adherent cells were typically seeded at 1×10⁵ cells per well in L-15 media (GIBCO) plus 5% foetal calf serum, 1% L-glutamine (100 μl/well) in 96 well tissue culture treated 96 well plates (Costar) and allowed to adhere overnight. The following day the cells were dosed with compound (diluted from 10 mM stock in DMSO using L-15 (with 5% FCS, 1% L-glutamine). Untreated control wells and wells containing a compound known to give 100% inhibition of BrdU incorporation were included on each plate. After 48 hours in the presence/absence of test compound the ability of the cells to incorporate BrdU over a 2 hour labelling period was determined using a Boehringer (Roche) Cell Proliferation BrdU ELISA kit (cat. No. 1 647 229) according to manufacturers directions. Briefly, 15 μl of BrdU labelling reagent (diluted 1:100 in media—L-15, 5% FCS, 1% L-glutamine) was added to each well and the plate returned to a humidified (+5% CO₂) 37° C. incubator for 2 hours. After 2 hours the labelling reagent was removed by decanting and tapping the plate on a paper towel. FixDenat solution (50 μl per well) was added and the plates incubated at room temperature for 45 minutes with shaking. The FixDenat solution was removed by decanting and tapping the inverted plate on a paper towel. The plate was then washed once with phosphate buffered saline (PBS) and 100 μl/well of Anti-BrdU-POD antibody solution (diluted 1:100 in antibody dilution buffer) added. The plate was then incubated at room temperature with shaking for 90 minutes. Unbound Anti-BrdU-POD antibody was removed by decanting and washing the plate 4 times with PBS before being blotted dry. TMB substrate solution was added (100 μl/well) and incubated for approximately 10 minutes at room temperature with shaking until a colour change was apparent. The optical density of the wells was then determined at 690 nm wavelength using a Titertek Multiscan plate reader. The values from compound treated, untreated and 100% inhibition controls were used to determine the dilution range of a test compound that gave 50% inhibition of BrdU incorporation. The compounds of the invention are active at 0.3 nM to 10000 nM in this test and in particular compound 5 in table 1 was active at 0.1 nM.

(d) In Vitro Cell Cycle Analysis Assay

This assay determines the ability of a test compound to arrest cells in specific phases of the cell cycle. Many different mammalian cell lines could be used in this assay and SW620 cells are included here as an example. SW620 cells were seeded at 7×10⁵ cells per T25 flask (Costar) in 5 ml L-15 (5% FCS, 1% L-glutamine). Flasks were then incubated overnight in a humidified 37° C. incubator with 5% CO₂. The following day, 5 μl of L-15 (5% FCS, 1% L-glutamine) carrying the appropriate concentration of test compound solubilised in DMSO was added to the flask. A no compound control treatments was also included (0.5% DMSO). The cells were then incubated for a defined time (24 hours) with compound. After this time the media was aspirated from the cells and they were washed with 5 ml of prewarmed (37° C.) sterile PBSA, then detached from the flask by brief incubation with trypsin and followed by resuspension in 5 ml of 1% Bovine Serum Albumin (BSA, Sigma-Aldrich Co.) in sterile PBSA. The samples were then centrifuged at 2200 rpm for 10 minutes. The supernatant was aspirated to leave 200 μl of the PBS/BSA solution. The pellet was resuspended in this 200 μl of solution by pipetting 10 times to create a single cell suspension. One ml of ice-cold 80% ethanol was slowly added to each cell suspension and the samples stored at −20° C. overnight or until required for staining. Cells were pelleted by centrifugation, ethanol aspirated off and pellets resuspended in 200 μl PBS containing 100 μg/ml RNAse (Sigma Aldrich) and 10 μg/ml Propidium Iodide (Sigma Aldrich). Cell suspensions were incubated at 37° C. for 30 min, a further 200 μl PBS added and samples stored in the dark at 4° C. overnight.

Each sample was then syringed 10 times using 21-gauge needle. The samples were then transferred to LPS tubes and DNA content per cell analysed by Fluorescence activated cell sorting (FACS) using a FACScan flow cytometer (Becton Dickinson). Typically 30,000 events were counted and recorded using CellQuest v1.1 software (Verity Software). Cell cycle distribution of the population was calculated using Modfit software (Verity Software) and expressed as percentage of cells with 2N (G0/G1), 2N-4N(S phase) and with 4N (G2/M) DNA content.

The compounds of the invention are active in this test at 0.3 nM to 10000 nM.

The invention will now be illustrated in the following non limiting examples, in which standard techniques known to the skilled chemist and techniques analogous to those described in these Examples may be used where appropriate, and in which, unless otherwise stated:

-   (i) evaporations were carried out by rotary evaporation in vacuo and     work up procedures were carried out after removal of residual solids     such as drying agents by filtration; -   (ii) operations were carried out at ambient temperature, typically     in the range 18-25° C. and in air unless stated, or unless the     skilled person would otherwise operate under an atmosphere of an     inert gas such as argon; -   (iii) column chromatography (by the flash procedure) and medium     pressure liquid chromatography (NPLC) were performed on Merck     Kieselgel silica (Art. 9385); -   (iv) yields are given for illustration only and are not necessarily     the maximum attainable; -   (v) the structures of the end products of the formula (I) were     generally confirmed by nuclear (generally proton) magnetic resonance     (NMR) and mass spectral techniques; proton magnetic resonance     chemical shift values were measured in deuterated dimethyl     sulphoxide (DMSO d₆) (unless otherwise stated) on the delta scale     (ppm downfield from tetramethylsilane) using one of the following     four instruments     -   Varian Gemini 2000 spectrometer operating at a field strength of         300 MHz     -   Bruker DPX300 spectrometer operating at a field strength of 300         MHz     -   JEOL EX 400 spectrometer operating at a field strength of 400         MHz     -   Bruker Avance 500 spectrometer operating at a field strength of         500 MHz         Peak multiplicities are shown as follows: s, singlet; d,         doublet; dd, double doublet; t, triplet; q, quartet; qu,         quintet; m, multiplet; br s, broad singlet. -   (vi) robotic synthesis was carried out using a Zymate XP robot, with     solution additions via a Zymate Master Laboratory Station and     stirred via a Stem RS5000 Reacto-Station at 25° C.; -   (vii) work up and purification of reaction mixtures from robotic     synthesis was carried out as follows: evaporations were carried out     in vacuo using a Genevac HT 4; column chromatography was performed     using either an Anachem Sympur MPLC system on silica using 27 mm     diameter columns filled with Merck silica (60 μm, 25 g); the     structures of the final products were confirmed by LCMS on a Waters     2890/ZMD micromass system using the following and are quoted as     retention time (RT) in minutes:

Column: waters symmetry C18 3.5 μm 4.6 × 50 mm Solvent A: H₂O Solvent B: CH₃CN Solvent C: methanol + 5% HCOOH Flow rate: 2.5 ml/min Run time: 5 minutes with a 4.5 minute gradient from 0-100% C Wavelength: 254 nm, bandwidth 10 nm Mass detector: ZMD micromass Injection volume 0.005 ml

-   (viii) Analytical LCMS for compounds which had not been prepared by     robotic synthesis was performed on a Waters Alliance HT system using     the following and are quoted as retention time (RT) in minutes:

Column: 2.0 mm × 5 cm Phenomenex Max-RP 80A Solvent A: Water Solvent B: Acetonitrile Solvent C: Methanol/1% formic acid or Water/1% formic acid Flow rate: 1.1 ml/min Run time: 5 minutes with a 4.5 minute gradient from 0-95% B + constant 5% solvent C Wavelength: 254 nm, bandwidth 10 nm Injection volume 0.005 ml Mass detector: Micromass ZMD

-   (ix) Preparative high performance liquid chromatography (HPLC) was     performed on either     -   Waters preparative LCMS instrument, with retention time (RT)         measured in minutes:

Column: β-basic Hypercil (21 × 100 mm) 5 μm Solvent A: Water/0.1% Ammonium carbonate Solvent B: Acetonitrile Flow rate: 25 ml/min Run time: 10 minutes with a 7.5 minute gradient from 0-100% B Wavelength: 254 nm, bandwidth 10 nm Injection volume 1-1.5 ml Mass detector: Micromass ZMD

-   -   Gilson preparative HPLC instrument, with retention time (RT)         measured in minutes:

Column: 21 mm × 15 cm Phenomenex Luna2 C18 Solvent A: Water + 0.2% trifluoracetic acid, Solvent B: Acetonitrile + 0.2% trifluoracetic acid Flow rate: 21 ml/min Runtime: 20 minutes with various 10 minute gradients from 5-100% B Wavelength: 254 nm, bandwidth 10 nm Injection volume 0.1-4.0 ml

-   (x) intermediates were not generally fully characterised and purity     was assessed by thin layer chromatography (TLC), HPLC, infra-red     (IR), MS or NMR analysis.     Particular examples of compounds of formula (I) are set out in the     following tables, in which * represents the point of attachment of     the groups in each table to the compound of formula (I) above each     table:

TABLE 1

Com- pound R^(x) R^(y) 1

3-fluorophenyl 2

3,5-difluorophenyl 3

3,5-difluorophenyl 4

3,5-difluorophenyl 5

3-fluorophenyl 6

2,3-difluorophenyl 7

2,3-difluorophenyl 8

3,5-difluorophenyl 9

3,5-difluorophenyl 10

3-fluorophenyl 11

3-fluorophenyl 12

3-fluorophenyl 13

2,3-difluorophenyl 14

3,5-difluorophenyl 15

2,3-difluorophenyl 16

2,3-difluorophenyl 17

2,3-difluorophenyl 18

3-fluorophenyl 19

2,3-difluorophenyl 20

3-fluorophenyl 21

2,3-difluorophenyl 22

2,3-difluorophenyl 23

2,3-difluorophenyl 24

3-fluorophenyl 25

2,3-difluorophenyl 26

3-fluorophenyl

TABLE 2

Compound R^(x) R^(y) 27

2,3-difluorophenyl

TABLE 3

Compound R^(x) R^(y) 28

2,3-difluorophenyl 29

2,3-difluorophenyl 30

2,3-difluorophenyl 31

2,3-difluorophenyl 32

2,3-difluorophenyl 33

2,3-difluorophenyl 34

2,3-difluorophenyl 35

2,3-difluorophenyl 36

2,3-difluorophenyl 37

3-fluorophenyl 38

3-fluorophenyl 39

3-fluorophenyl 40

3-fluorophenyl 41

3-fluorophenyl 42

3-fluorophenyl 43

3-fluorophenyl 44

3-fluorophenyl

TABLE 4

Compound R^(x) R^(y) 45

2,3-difluorophenyl 46

2,3-difluorophenyl 47

2,3-difluorophenyl 48

2,3-difluorophenyl 49

2,3-difluorophenyl

TABLE 5

Compound R^(x) R^(y) 50

3-fluorophenyl

EXAMPLE 1 Preparation of Compound 1 in Table 1—{1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-4-yl}methyl dihydrogen phosphate

Di(tert-butyl) {1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-4-yl}methyl phosphate (400 mg, 0.53 mmol) was suspended in dioxane (20 ml) and treated with a solution of hydrochloric acid (4.0 N) in dioxane (795 μl, 3.18 mmol) at ambient temperature for 15 hours. The solid was recovered by filtration, washed with dioxane, dried in vacuo at 50° C. to yield compound 1 in table 1 (360 mg, 94% yield):

¹H-NMR (DMSO d₆, AcOD): 8.88 (s, 1H), 8.27 (s, 1H), 7.61 (m, 1H), 7.35 (m, 3H), 6.84 (m, 1H), 6.81 (s, 1H), 4.28 (m, 2H), 3.98 (s, 3H), 3.83 (s, 2H), 3.75 (t, 2H), 3.58 (d, 2H), 3.26 (m, 2H), 3.26 (m, 2H), 2.32 (m, 2H), 1.85 (m, 3H), 1.54 (m, 2H):

MS (+ve ESI): 644.5 (M+H)⁺.

Di(tert-butyl) {1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-4-yl}methyl phosphate, used as the starting material, was obtained as follows:

-   a) A mixture of 4-benzyloxy-3-methoxybenzaldehyde (157 g, 649 mmol),     sodium acetate (106 g, 1.29 mol), hydroxylamine hydrochloride (90 g,     1.29 mol) and acetic acid (500 ml) was refluxed for 21 hours. The     solvent was evaporated and ice/water (1000 ml) was added to the     residue forming a sticky solid. The mixture was neutralised with     aqueous sodium hydroxide solution then extracted with     dichloromethane (2×500 ml). The organic solution was washed with 1.0     N sodium hydroxide (100 ml), brine (100 ml) and then dried over     magnesium sulphate. Solvent evaporation, trituration of the residue     with hexane:ethyl acetate (3:1) and collection of the solid by     vacuum filtration yielded 4-benzyloxy-3-methoxybenzonitrile (123 g,     80% yield) as a brown solid:

¹H-NMR (DMSO d₆): 7.38 (m, 7H), 7.19 (m, 1H), 5.18 (s, 2H), 3.80 (s, 3H): MS (−ve ESI): 238 (M−H)⁻.

-   b) Acetic acid (17 ml) was added slowly to nitric acid (40 ml, 440     mmol) at 5° C. Powdered 4-benzyloxy-3-methoxybenzonitrile (10 g, 42     mmol) was added and the mixture warmed to 23° C. over 10 minutes. An     exotherm occurred and the temperature was controlled at <30° C.     using an ice bath. The mixture was stirred at 23° C. for 20 hours     then poured into ice/water (1000 ml). After stirring for two hours     the yellow solid was collected by suction filtration, washed with     water and dried to yield 4-benzyloxy-3-methoxy-6-nitrobenzonitrile     (10.1 g, 85% yield) as a yellow solid:

¹H-NMR (DMSO d₆): 7.95 (s, 1H), 7.70 (s, 1H), 7.40 (m, 5H), 5.30 (s, 2H), 3.95 (s, 3H):

MS (−ve ESI): 283 (M−H)⁻.

-   c) A mixture of 4-benzyloxy-3-methoxy-6-nitrobenzonitrile (46 g, 162     mmol), sodium bicarbonate (95 g, 1.13 mol), water (750 ml),     dichloromethane (550 ml) and tetrabutylammonium chloride (30 g, 108     mmol) was rapidly stirred at 20° C. and treated with sodium     dithionite (66 g, 379 mmol) portionwise over 2 hours. The mixture     was stirred for a further hour then the phases separated. The     aqueous phase was extracted with dichloromethane (2×200 ml) and the     combined organic solution washed with water (300 ml) and dried over     magnesium sulphate. The solution was concentrated to 250 ml and 4.0     M hydrochloric acid in 1,4-dioxane (150 ml, 0.6 mol) added, then     diluted with diethyl ether (1000 ml) and cooled on ice. The     resulting solid was collected by vacuum filtration and washed with     diethyl ether. The solid was stirred in methanol (1000 ml) and     sodium bicarbonate solution (800 ml) added to pH 8 and stirred for 1     hour. The solid was collected by vacuum filtration, washed with     water then methanol and dried in vacuo to yield     2-amino-4-(benzyloxy)-5-methoxybenzonitrile (34 g, 82% yield) as     light brown solid:

¹H-NMR (DMSO d₆): 7.40 (m, 5H), 6.90 (s, 1H), 6.50 (s, 1H), 5.60 (br s, 2H), 5.02 (s, 2H), 3.65 (s, 3H):

MS (+ve ESI): 254 (M+H)⁺.

-   d) 2-amino-4-(benzyloxy)-5-methoxybenzonitrile (100 g, 394 mmol) in     toluene (1400 ml) was treated with dimethylformamide dimethylacetal     (100 ml, 940 mmol) at reflux with slow distillation of solvent to     maintain the internal temperature at 105° C. After 3 hours the     solution was cooled and filtered to remove a small amount of solid.     The filtrate was evaporated in vacuo and the residue triturated with     diethyl ether and the solid collected by vacuum filtration and dried     in vacuo to yield N′-(5-(benzyloxy)-2-cyano-4-methoxyphenyl)     -N,N-dimethylimidoformamide(110 g, 90% yield) as a brown solid:

¹H-NMR (DMSO d₆): 7.90 (s, 1H), 7.40 (m, 5H), 7.10 (s, 1H), 6.88 (s, 1H), 5.15 (s, 2H), 3.70 (s, 3H), 3.02 (s, 3H), 2.95 (s, 3H):

MS (+ve ESI): 310 (M+H)⁺

MS (−ve ESI): 308 (M−H)⁻.

-   e)     N-(5-(benzyloxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide     (110 g, 356 mmol) and trifluoroacetic acid (600 ml) were refluxed     together for 15 min. Evaporation and co-evaporation with toluene,     trituration with diethyl ether and collection of the solid by vacuum     filtration and drying in vacuo yielded     N′-(2-cyano-5-hydroxy-4-methoxyphenyl) -N,N-dimethylimidoformamide     (112 g, 95% yield) as a light brown trifluoroacetate salt:

¹H-NMR (DMSO d₆): 8.39 (s, 1H), 7.38 (s, 1H), 6.90 (s, 1H), 3.80 (s, 3H), 3.25 (s, 3H), 3.17 (s, 3H):

MS (+ve ESI): 220 (M+H)⁺

MS (−ve ESI): 218 (M−H)⁻.

-   f) A mixture of     N′-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamide     (21.9 g, 66 mmol), cesium carbonate (998 g, 300 mmol) and     1-bromo-3-chloropropane (11 ml, 110 mmol) in acetonitrile (300 ml)     was refluxed for 1 hour. The reaction mixture was cooled and the     solvent evaporated in vacuo. The residue in water (200 ml) was     extracted with dichloromethane (2×150 ml). The organic solution was     washed with brine (50 ml) and dried over magnesium sulphate. Solvent     was evaporated in vacuo and the residue triturated with diethyl     ether. The solid was collected by vacuum filtration and dried in     vacuo to yield N′-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)     -N,N-dimethylimidoformamide (17.7 g, 91% yield) as a white solid:

¹H-NMR (DMSO d₆): 8.89 (s, 1H), 7.07 (s, 1H), 6.75 (s, 1H), 4.15 (t, 2H), 3.77 (t, 2H), 3.70 (s, 3H), 3.05 (s, 3H), 2.95 (s, 3H), 2.18 (m, 2H):

MS (+ve ESI): 296.4 (M+H)⁺.

-   g)     N′-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide     (230 mg, 0.78 mmol) in acetic acid (0.7 ml) was reacted with methyl     (5-amino-1H-pyrazol-3-yl)acetate (CAS 174891-10-2; WO 95/33724) (110     mg, 0.74 mmol) at reflux for 1 hour. The mixture was cooled, the     acetic acid evaporated, and the residue purified by chromatography     on silica gel, eluting with dichloromethane/1% methanolic ammonia     (90:10), to give methyl     (5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-3-yl)acetate     (219 mg, 69% yield) as a cream solid:

¹H-NMR (DMSO d₆, TFA): 8.93 (s, 1H), 8.28 (s, 1H), 7.32 (s, 1H), 6.80 (s, 1H), 4.02 (m, 2H), 4.00 (s, 3H), 3.75-3.85 (m, s, 4H), 3.65 (s, 3H), 2.30 (m, 2H), 1.90 (s, 3H):

MS (+ve ESI): 406.5 (M+H)⁺.

-   h) Methyl     (5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-3-yl)acetate     (100 mg, 0.247 mmol) in tetrahydrofuran (1.2 ml)/water (0.6 ml), was     reacted with lithium hydroxide (21 mg, 0.493 mmol) at ambient     temperature over night. The mixture was acidified with 6.0 N     hydrochloric acid to pH 4 and the solid was recovered by filtration,     washed with water and dried to give     (5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-3-yl)acetic     acid (72 mg, 75% yield) as a beige solid:

¹H-NMR (DMSO d₆, TFA): 8.95 (s, 1H), 8.28 (s, 1H), 7.32 (s, 1H), 6.80 (s, 1H), 4.33 (m, 2H), 4.00 (s, 3H), 3.83 (m, 2H), 3.74 (s, 2H), 2.40-2.50 (m, 2H):

MS (+ve ESI): 392.5, 394.5 (M+H)⁺.

-   i)     (5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-3-yl)     acetic acid (7.83 g, 20 mmol) in dimethylformamide (78 ml) was     reacted with 3-fluoroaniline (2.44 g, 22 mmol) in the presence of     1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (4.2 g,     22 mmol), 2-hydroxypyridin-1-oxide (2.22 g, 20 mmol) and     diisopropylethylamine (2.8 g, 22 mmol) at 50° C. for 1.7 hours. The     solvent was removed by evaporation under vacuum, the residue was     triturated with water (twice), and purified by silica gel     chromatography, eluting with dichloromethane:methanol (95:3 to     85:15) to give 2-(5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)     amino)-1H-pyrazol-3-yl)-N-(3-fluorophenyl) acetamide (4.5 g, 46%     yield) as a beige solid:

¹H-NMR (DMSO d₆): 8.47 (s, 1H), 8.02 (s, 1H), 7.60-7.68 (m, 1H), 7.30-7.41 (m, 2H), 7.20 (s, 1H), 6.88 (m, 1H), 6.84 (s, 1H), 4.27 (m, 2H), 3.96 (s, 3H), 3.84 (m, 2H), 3.78 (s, 2H), 2.26 (m, 2H):

MS (+ve ESI): 485.6 (M+H)⁺.

-   j) Piperidin-4-ylmethanol (115 mg, 1 mmol) was added to a solution     of     2-(5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-3-yl)-N-(3-fluorophenyl)     acetamide (121 mg, 0.25 mmol) in dimethylacetamide (1 ml) and the     reaction was heated at 90° C. for 9 hours. The reaction was cooled     to ambient temperature and the volatile substances removed in vacuo.     Purification by reverse phase hplc yielded     N-(3-fluorophenyl)-2-{3-[(7-{3-[4(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (80 mg, 57% yield) as an off-white solid:

¹H-NMR (DMSO d₆, TFA): 8.96 (s, 1H), 8.30 (s, 1H), 7.63 (m, 1H), 7.36 (m, 3H), 6.90 (m, 1H), 6.84 (s, 1H), 4.30 (t, 2H), 4.01 (s, 3H), 3.85 (s, 2H), 3.62 (d, 2H), 3.32 (d, 2H), 3.27 (m, 2H), 2.98 (t, 2H), 2.29 (m, 2H), 1.90 (d, 2H), 1.67 (m, 1H), 1.42 (m, 2H):

MS (+ve ESI): 564.6 (M+H)⁺.

-   k)     N-(3-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (450 mg, 1 mmol) was dissolved in dimethylformamide (2 ml),     tetrazole (224 mg, 4 mmol) and di-tert-butyl-diethyl-phosphoramidite     (479 μl, 2 mmol) were added to the mixture at ambient temperature,     and stirring was continued for 3 hours under argon. The reaction     mixture was then cooled to −60° C. and a solution of     monoperoxyphthalic acid magnesium salt (297 mg, 0.6 mmol) in     dimethylformamide (1.5 ml) was slowly added to the reaction mixture.     This mixture was then stirred for 1.5 hours at 60° C., sodium     metabisulphite (1.5 g, 10 mmol) in solution in water (2 ml) was then     added and the reaction mixture was slowly allowed to warm to ambient     temperature, evaporated, and the residue was purified by silica gel     chromatography, eluting with dichloromethane: 3.0 N methanolic     ammonia (100:0 to 92:8), to give di(tert-butyl)     {1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-4-yl}methyl     phosphate (420 mg, 70% yield) as a cream solid:

¹H-NMR (DMSO d₆): 8.46 (s, 1H), 7.99 (s, 1H), 7.63 (d, 1H), 7.36 (m, 2H), 7.35 (s, 1H), 7.15 (s, 1H), 6.90 (m, 1H), 6.88 (s, 1H), 4.17 (t, 2H), 3.95 (s, 3H), 3.77 (s, 2H), 3.72 (t, 2H), 2.91 (d, 2H), 2.46 (t, 2H), 1.96 (m, 4H), 1.65 (m, 2H), 1.58 (m, 1H), 1.41 (s, 18H), 1.25 (m, 2H):

MS (+ve ESI): 756.6 (M+H)⁺.

EXAMPLE 2 Preparation of Compound 2 in Table 1—2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di(tert-butyl) 2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino-]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl phosphate (320 mg, 0.428 mmol) yielded compound 2 in table 1 (260 mg, 86% yield) as an off-white solid:

¹H-NMR (DMSO d₆, CD₃COOD): 8.92 (s, 1H), 8.31 (s, 1H), 7.41 (m, 3H), 6.88 (t, 1H), 6.84 (s, 1H), 4.32 (m, 4H), 3.97 (s, 3H), 3.89 (s, 2H), 3.42 (m, 6H), 2.32 (m, 2H), 1.31 (t, 3H):

MS (+ve ESI): 636.4 (M+H)⁺.

Di(tert-butyl) 2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl phosphate, used as the starting material, was obtained as follows:

-   a) A suspension of     3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetic     acid (3.91 g, 10 mmol) in dimethylformamide (20 ml) was reacted with     3,5-difluoroaniline (1.42 g, 11 mmol) in the presence of     1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (2.01 g,     10.5 mmol) and 2-hydroxypyridine-1-oxide (1.11 g, 10 mmol) at 60° C.     for 1.75 hours. The solvent was evaporated in vacuo and the residue     was triturated twice with water. The resulting wet paste was     dissolved in a mixture of dichloromethane:water (80:20), adsorbed     onto silica gel and purified by chromatography on silica gel,     eluting with dichloromethane:methanol (95:5 to 85:15) to give     2-(5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-3-yl)-N-(3,5-difluorophenyl)     acetamide (2.45 g, 49% yield) as a beige solid:

¹H-NMR (DMSO d₆): 8.47 (s, 1H), 8.02 (s, 1H), 7.36 (m, 2H), 7.20 (s, 1H), 6.94 (t, 1H), 6.84 (s, 1H), 4.27 (m, 2H), 3.96 (s, 3H), 3.83 (m, 2H), 3.79 (s, 2H), 2.27 (m, 2H):

MS (+ve ESI): 503.5, 505.5 (M+H)⁺.

-   b) An analogous reaction to that described in example 1j, but     starting with 2-(ethylamino)ethanol (89 mg, 1 mmol) and     2-(5-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)-1H-pyrazol-3-yl)-N-(3,5-difluorophenyl)     acetamide (130 mg, 0.26 mmol) yielded     N-(3,5-difluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (124 mg, 86% yield) as an off-white solid:

¹H-NMR (DMSO d₆, TFA): 8.96 (s, 1H), 8.30 (s, 1H), 7.35 (m, 2H), 7.33 (s, 1H), 6.90 (m, 1H), 6.84 (s, 1H), 4.30 (m, 2H), 4.01 (s, 3H), 3.86 (s, 2H), 3.78 (t, 2H), 3.30 (m, 6H), 2.29 (m, 2H), 1.27 (t, 3H):

MS (+ve ESI): 556.5 (M+H)⁺.

-   c) An analogous reaction to that described in example 1k, but     starting with     N-(3,5-difluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (400 mg, 0.72 mmol) yielded di(tert-butyl)     2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl     phosphate (320 mg, 60% yield) as an off-white solid: tk

¹H-NMR (DMSO d₆): 8.36 (s, 1H), 7.88 (s, 1H), 7.26 (m, 2H), 7.04 (s, 1H), 6.83 (t, 2H), 6.73 (s, 1H), 4.07 (m, 2H), 3.85 (s, 3H), 3.77 (q, 2H), 2.68 (s, 2H), 2.55 (m, 4H), 2.43 (m, 2H), 1.81 (m, 2H), 0.88 (t, 3H):

MS (+ve ESI): 748.5 (M+H)⁺.

EXAMPLE 3 Preparation of Compound 3 in Table 1—{(2S)-1-[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di(tert-butyl) {(2S)-1-[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl phosphate (130 mg, 0.171 mmol) yielded compound 3 in table 1 (91 mg, 74% yield):

¹H-NMR (DMSO d₆, CD₃COOD): 8.91 (s, 1H), 8.29 (s, 1H), 7.40 (m, 3H), 6.89 (t, 1H), 6.82 (s, 1H), 4.31 (m, 2H), 4.20 (m, 2H), 4.00 (s, 3H), 3.88 (s, 2H), 3.80 (m, 1H), 3.70 (m, 1H), 3.60 (m, 1H), 3.28 (m, 1H), 3.23 (m, 1H), 2.30 (m, 2H), 2.20 (m, 1H), 2.03 (m, 1H), 1.95 (m, 1H), 1.82 (m, 1H):

MS (+ve ESI): 648.3 (M+H)⁺.

di(tert-butyl) {(2S)-1-[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl phosphate, used as the starting material, was obtained as follows:

-   a) An analogous reaction to that described in example 2b, but     starting with L-prolinol (101 mg, 1 mmol) yielded     N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (85 mg, 57% yield) as an off-white solid:

¹H-NMR (DMSO d₆, TFA): 8.96 (s, 1H), 8.30 (s, 1H), 7.30-7.40 (m, 3H), 6.85-6.95 (m, 1H), 6.84 (s, 1H), 4.30 (m, 2H), 4.01 (s, 3H), 3.86 (s, 2H), 3.72-3.82 (m, 1H), 3.50-3.70 (m, 4H), 3.15-3.30 (m, 2H), 2.25-2.40 (m, 2H), 1.95-2.20 (m, 2H), 1.85-1.95 (m, 1H), 1.70-1.85 (m, 1H):

MS (+ve ESI): 568.6 (M+H)⁺.

-   b)     N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (650 mg, 1.14 mmol) was dissolved in dimethylacetamide (4 ml).     Tetrazole (160 mg, 2.3 mmol) and     di-tert-butyl-diethylphosphoramidite (637 μl, 2.3 mmol) were added     to the mixture and stirring was continued at ambient temperature     under argon for 3 hours. The reaction mixture was then diluted with     dichloromethane (50 ml) and washed with a saturated solution of     sodium bicarbonate. The organic phase was recovered, dried over     magnesium sulphate, filtered and concentrated. The crude product was     dissolved in tetrahydrofuran (18 ml) at 0° C. and hydrogen peroxide     (30%, 335 μl) was added to the solution, which was stirred for 15     hours at ambient temperature. The mixture was then cooled to 0° C.     and sodium metabisulphite (1.08 g) in water (5 ml) was added at 0°     C., and the reaction was allowed to warm to ambient temperature. The     mixture was diluted with ethyl acetate (50 ml), washed with a     saturated solution of sodium bicarbonate. The organic phase was     recovered, dried over magnesium sulphate, filtered and concentrated     in vacuo. The crude product was purified by chromatography on silica     gel, eluting with dichloromethane:methanol: 3.0 N methanolic ammonia     (95:5:0 to 95:0:5), to give di(tert-butyl)     {(2S)-1-[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     phosphate (133 mg, 15% yield) as an off-white solid:

¹H-NMR (DMSO d₆): 8.44 (s, 1H), 7.96 (s, 1H), 7.35 (m, 2H), 7.13 (s, 1H), 6.92 (m, 1H), 6.82 (s, 1H), 4.18 (m, 2H), 3.93 (s, 3H), 3.75 (m, 3H), 3.56 (m, 1H), 3.08 (m, 1H), 2.92 (m, 1H), 2.67 (m, 1H), 2.46 (m, 1H), 2.20 (q, 1H), 1.95 (m, 2H), 1.83 (m, 1H), 1.68 (m, 2H), 1.59 (m, 1H), 1.38 (s, 18H):

MS (+ve ESI): 760.5 (M+H)⁺.

EXAMPLE 4 Preparation of Compound 4 in Table 1—{(2R)-1-[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di(tert-butyl) {(2R)-1-[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl phosphate (350 mg, 0.46 mmol) yielded compound 4 in table 1 (305 mg, 92% yield) as an off-white solid:

¹H-NMR (DMSO d₆): 8.90 (s, 1H), 8.29 (s, 1H), 7.40 (m, 3H), 6.87 (t, 1H), 6.81 (s, 1H), 4.31 (m, 2H), 4.20 (m, 2H), 4.00 (s, 3H), 3.88 (s, 2H), 3.80 (m, 1H), 3.70 (m, 1H), 3.60 (m, 1H), 3.28 (m, 1H), 3.23 (m, 1H), 2.32 (m, 2H), 2.20 (m, 1H), 2.04 (m, 1H), 1.95 (m, 1H), 1.84 (m, 1H):

MS (+ve ESI): 648.4 (M+H)⁺.

di(tert-butyl) {(2R)-1-[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl phosphate, used as the starting material, was obtained as follows:

-   a) An analogous reaction to that described in example 2b, but     starting with D-prolinol (101 mg, 1 mmol) yielded     N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (85 mg, 57% yield) as an off-white solid:

¹H-NMR (DMSO d₆, TFA): 8.96 (s, 1H), 8.30 (s, 1H), 7.35 (m, 2H), 7.33 (s, 1H), 6.91 (m, 1H), 6.84 (s, 1H), 4.31 (m, 2H), 4.01 (s, 3H), 3.86 (s, 2H), 3.78 (m, 1H), 3.63 (m, 4H), 3.22 (m, 2H), 2.30 (m, 2H), 2.13 (m, 1H), 2.03 (m, 1H), 1.80 (m, 1H), 1.78 (m, 1H):

MS (+ve ESI): 568.5 (M+H)⁺.

-   b) An analogous reaction to that described in example 3b, but     starting with     N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (600 mg, 1.06 mmol) yielded di(tert-butyl)     {(2R)-1-[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     phosphate (361 mg, 45% yield) as an off-white solid:

¹H-NMR (DMSO d₆): 8.45 (s, 1H), 7.96 (s, 1H), 7.35 (m, 2H), 7.13 (s, 1H), 6.93 (m, 1H), 6.82 (s, 1H), 4.18 (m, 2H), 3.95 (s, 3H), 3.75 (m, 3H), 3.58 (m, 1H), 3.08 (m, 1H), 2.93 (m, 1H), 2.67 (m, 1H), 2.46 (m, 1H), 2.22 (q, 1H), 1.96 (m, 2H), 1.86 (m, 1H), 1.69 (m, 2H), 1.61 (m, 1H), 1.38 (s, 18H):

MS (+ve ESI): 760.5 (M+H)⁺.

EXAMPLE 5 Preparation of Compound 5 in Table 1—{(2S)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di(tert-butyl) {(2S)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl phosphate (282 mg, 0.38 mmol) yielded compound 5 in table 1 (265 mg, 97% yield) as an off-white solid:

¹H-NMR (DMSO d₆): 8.90 (s, 1H), 8.30 (s, 1H), 7.66 (d, 1H), 7.46 (s, 1H), 7.40 (m, 2H), 6.90 (m, 1H), 6.81 (s, 1H), 4.31 (m, 2H), 4.20 (m, 2H), 4.00 (s, 3H), 3.88 (s, 2H), 3.80 (m, 1H), 3.70 (m, 1H), 3.60 (m, 1H), 3.28 (m, 1H), 3.22 (m, 1H), 2.32 (m, 2H), 2.20 (m, 1H), 2.04 (m, 1H), 1.95 (m, 1H), 1.84 (m, 1H):

MS (+ve ESI): 630.6 (M+H)⁺.

di(tert-butyl) {(2S)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl phosphate, used as the starting material, was obtained as follows:

-   a) An analogous reaction to that described in example 1j, but     starting with L-prolinol (121 mg, 0.25 mmol) yielded     N-(3-fluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (86 mg, 62% yield) as an off-white solid:

¹H-NMR (DMSO d₆, TFA): 8.95 (s, 1H), 8.29 (s, 1H), 7.60-7.70 (m, 1H), 7.28-7.40 (m, 3H), 6.85-6.92 (m, 1H), 6.82 (s, 1H), 4.31 (m, 2H), 4.00 (s, 3H), 3.84 (s, 2H), 3.70-3.80 (m, 1H), 3.50-3.70 (m, 4H), 3.10-3.30 (m, 2H), 2.20-2.40 (m, 2H), 2.05-2.20 (m, 1H), 1.95-2.10 (m, 1H), 1.85-1.95 (m, 1H), 1.70-7.85 (m, 1H):

MS (+ve ESI): 549.6 (M+H)⁺.

-   b) An analogous reaction to that described in example 1k, but     starting with     N-(3-fluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (275 mg, 0.5 mmol) yielded di(tert-butyl)     {(2S)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     phosphate (255 mg, 69% yield) as an off-white solid:

¹H-NMR (DMSO d₆): 8.46 (s, 1H), 7.98 (s, 1H), 7.64 (d, 1H), 7.36 (m, 2H), 7.15 (s, 1H), 6.89 (m, 1H), 6.81 (s, 1H), 4.18 (m, 2H), 3.93 (s, 3H), 3.75 (m, 3H), 3.58 (m, 1H), 3.11 (m, 1H), 2.97 (m, 1H), 2.67 (n, 1H), 2.46 (m, 1H), 2.22 (m, 1H), 1.98 (m, 2H), 1.82 (m, 1H), 1.71 (m, 2H), 1.62 (m, 1H), 1.38 (s, 18H):

MS (+ve ESI): 742.7 (M+H)⁺.

EXAMPLE 6 Preparation of compound 6 in table 1—2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](propyl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](propyl)amino]ethyl phosphate (316 mg, 0.41 mmol) yielded compound 6 in table 1 (300 mg, 100% yield):

¹H-NMR (DMSO d₆, TFA): 8.96 (s, 1H), 8.31 (s, 1H), 7.75 (m, 1H), 7.36 (s, 1H), 7.20 (m, 2H), 6.84 (s, 1H), 4.31 (t, 2H), 4.24 (m, 2H), 4.01 (s, 3H), 3.94 (s, 2H), 3.50 (m, 2H), 3.38 (m, 2H), 3.19 (m, 2H), 2.32 (m, 2H), 1.74 (m, 2H), 0.95 (t, 3H):

MS (+ve ESI): 650.3 (M+H)⁺.

di-tert-butyl 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](propyl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a)     5-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-3-yl)acetic     acid (3.91 g, 10 mmol) was suspended in pyridine (20 ml) in the     presence of 2,3-difluoroaniline (1.55 g, 12 mmol) under argon at     0° C. Phosphorus oxychloride (1.53 g, 10 mmol) in ethyl acetate     (2 ml) was slowly added at 0° C. and the resulting mixture was     allowed to warm to ambient temperature over 1.5 hours. The reaction     mixture was diluted with ethyl acetate (150 ml) and diethyl ether     (50 ml) resulting in the precipitation of a red solid. The solid was     recovered by suction filtration, dried and re-suspended in water     (100 ml). The mixture was cooled to 0° C. and the pH adjusted to 7     by addition of 1.5 N aqueous ammonium hydroxide solution. After 15     minutes stirring, the solid was recovered, dried, and purified by     chromatography on silica gel, eluting with     dichloromethane:methanol (9515) and increased polarity to     dichloromethane:methanolic ammonia (95:2) to yield     2-(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(2,3-difluorophenyl)acetamide     as a pink solid (2.55 g, 50% yield):

¹H-NMR (DMSO d₆, TFA): 8.94 (s, 1H), 8.28 (s, 1H), 7.73 (m, 1H), 7.33 (s, 1H), 7.15-7.22 (m, 1H), 6.84 (s, 1H), 4.30 (m, 2H), 4.00 (s, 3H), 3.94 (s, 2H), 3.84 (m, 2H), 2.30 (m, 2H):

MS (+ve ESI): 503.9 (M+H)⁺.

-   b) 2-(propylamino)ethanol (700 mg, 68 mmol) and potassium iodide     (564 mg, 34 mmol) were added to a solution of     2-(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(2,3-difluorophenyl)acetamide     (855 mg, 17 mmol) in dimethylacetamide (8 ml) and the reaction     heated at 85° C. for 5 hours. The solvent was evaporated in vacuo,     the residue triturated with diethyl ether and the solid was     collected by suction filtration. Purification by chromatography on     silica gel, eluting with, dichloromethane/methanol (90:10) to     dichloromethane/methanol/ammonia (7.0 N) to give     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (650 mg, 67% yield):

¹H-NMR (DMSO d₆, TFA): 8.96 (s, 1H), 8.30 (s, 1H), 7.75 (m, 1H), 7.33 (s, 1H), 7.18-7.22 (m, 2H), 6.84 (s, 1H), 4.30 (m, 2H), 4.00 (s, 3H), 3.94 (s, 2H), 3.78 (m, 2H), 3.30-3.45 (m, 2H), 3.28 (m, 2H), 3.15-3.20 (m, 2H), 2.28 (m, 2H), 1.73 (m, 2H), 0.95 (t, 3H):

MS (+ve ESI): 570.3 (M+H)⁺.

-   c) Di-tert-butyl-diethylphosphoramidite (417 μm, 1.5 mmol) was     slowly added to a solution of     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)     amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (569 mg, 1 mmol) in dimethylformamide (2.5 ml) in the presence of     tetrazole (210 mg, 3 mmol) at ambient temperature under argon. The     mixture was stirred at ambient temperature for 1.5 hours, cooled to     −10° C. and hydrogen peroxide (134 μm of a 9.0 N solution, 1.2 mmol)     was slowly added. The resulting mixture was stirred at ambient     temperature for 2 hours. Sodium metabisulphite (570 mg, 3 mmol) in     water (2 ml) was then added at 0° C. and the mixture was stirred at     ambient temperature for 0.5 hour. The mixture was concentrated,     dichloromethane/methanol (8:2) was added before the solid was     filtered and washed with dichloromethane/methanol. Concentration of     the filtrate in vacuo followed by chromatography on silica gel,     eluting with dichloromethane/methanol (90:10) to     dichloromethane/methanol/ammonia (7.0 N) (90:10:1), yielded     di-tert-butyl     2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     phosphate as an off-white solid (319 mg, 42% yield):

¹H-NMR (DMSO d₆, TFA): 8.95 (s, 1H), 8.29 (s, 1H), 7.72 (m, 1H), 7.33 (s, 1H), 7.18 (m, 2H), 6.84 (s, 1H), 4.20-4.35 (m, 4H), 4.00 (s, 3H), 3.94 (s, 2H), 3.53 (m, 2H), 3.39 (m, 2H), 3.20 (m, 2H), 2.30 (m, 2H), 1.73 (m, 2H), 1.44 (s, 18H), 0.95 (t, 3H):

MS (+ve ESI): 762.5 (M+H)⁺.

Compound 6, synthesised above as the dihydrochloride salt, could also be prepared as the free base according to the following method:

-   d)     2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     dihydrogen phosphate dihydrochloride (10 g, 13 mmol) was solubilized     in methanol (300 ml) and cyclohexane oxide (12,7 g, 130 mmol) was     added to the solution. The solution was stirred at ambient     temperature for 48 hours, during which time a white solid     precipitated. The mixture was diluted with diethyl ether (100 ml)     and the solid was recovered by filtration, washed with ether and     dried in vacuo to give     2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     dihydrogen phosphate (7.65 g, 88% yield) as a light yellow powder:

¹H-NMR (DMSO d₆, TFA): 8.96 (s, 1H), 8.30 (s, 1H), 7.74 (m, 1H), 7.34 (s, 1H), 7.19 (m, 2H), 6.84 (s, 1H), 4.31 (m, 2H), 4.24 (m, 2H), 4.01 (s, 3H), 3.94 (s, 2H), 3.51 (m, 2H), 3.38 (m, 2H), 3.18 (m, 2H), 2.29 (m, 2H), 1.73 (m, 2H), 0.96 (t, 3H):

MS (+ve ESI): 650 (M+H)⁺.

C₂₈H₃₄F₂N₇O₇P+1.04H₂O +0.03 Et₂O requires C, 50.37%; H, 5.47%; N, 14.62%; Found C, 50.02%; H, 5.54%; N, 14.48%.

EXAMPLE 7 Preparation of compound 7 in table 1—2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl phosphate (465 mg, 0.6 mmol) yielded compound 7 in table 1 (480 mg, 100% yield):

¹H-NMR (DMSO 44, TFA): 8.95 (s, 1H), 8.34 (s, 1H), 7.76 (m, 1H), 7.43 (s, 1H), 7.18 (m, 2H), 6.86 (s, 1H), 4.33 (m, 4H), 4.02 (s, 3H), 3.97 (s, 2H), 3.54 (m, 2H), 3.40 (m, 2H), 3.12 (d, 2H), 2.35 (m, 2H), 2.17 (m, 1H), 1.05 (d, 6H).

di-tert-butyl 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a) A cooled (−60° C.) solution of ethylene oxide (5.28 g, 120 mmol)     in methanol (14 ml), was added slowly to a solution of isobutylamine     (30.7 g, 420 mmol) in methanol (100 ml) at −65° C. under argon. The     mixture was allowed to warmn to ambient temperature over 14 hours,     concentrated in vacuo and the residual oil was purified by     distillation (b.p. 130° C./0.5 mmHg) to yield     2-(isobutylamino)ethanol (11 g, 78% yield):

¹H-NMR (DMSO d₆): 4.40 (m, 1H), 3.42 (m, 2H), 2.50 (m, 2H), 2.30 (d, 2H), 1.63 (m, 1H), 0.85 (d, 6H).

-   b) An analogous reaction to that described in example 6b, but     starting with 2-(isobutylamino)ethanol (936 mg, 80 mmol) and heating     at 90° C. for 3.5 hours, yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as an off-white solid (810 mg, 69% yield):

¹H-NMR (DMSO d₆, TFA): 8.96 (s, 1H), 8.30 (s, 1H), 7.45 (m, 1H), 7.34 (s, 1H), 7.21 (m, 2H), 6.84 (s, 1H), 4.31 (m, 2H), 4.00 (s, 3H), 3.95 (s, 2H), 3.81 (m, 2H), 3.36 (m, 2H), 3.30 (m, 2H), 3.12 (m, 1H), 3.06 (m, 1H), 2.31 (m, 2H), 2.13 (m, 1H), 1.01 (d, 6H):

MS (+ve ESI): 584.3 (M+H)⁺.

-   c) An analogous reaction to that described to that described in     example 6c, but starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (4.96 mg, 8.5 mmol) yielded di-tert-butyl     2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl     phosphate (4.7 g, 71% yield):

¹H-NMR (DMSO d₆, TFA): 8.96 (s, 1H), 8.30 (s, 1H), 7.74 (m, 1H), 7.34 (s, 1H), 7.19 (m, 2H), 6.84 (s, 1H), 4.30 (m, 4H), 4.00 (s, 3H), 3.94 (s, 2H), 3.54 (m, 2H), 3.39 (m, 2H), 3.12 (d, 2H), 2.32 (m, 2H), 2.14 (m, 1H), 1.45 (s, 18H), 1.02 (d, 6H)

MS (+ve ESI): 776.8 (M+H)⁺.

EXAMPLE 8 Preparation of compound 8 in table 1—2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl phosphate (325 mg, 0.42 mmol) yielded compound 8 in table 1 (315 mg, 98% yield):

¹H-NMR (DMSO d₆, TFA): 8.95 (s, 1H), 8.32 (s, 1H), 7.39 (d, 1H), 7.38 (s, 1H), 7.36 (d, 1H), 6.91 (t, 1H), 6.84 (s, 1H), 4.30 (m, 2H), 4.01 (s, 3H), 3.87 (s, 2H), 3.53 (m, 2H), 3.39 (m, 2H), 3.11 (d, 1H), 2.32 (m, 2H), 2.14 (m, 1H), 1.02 (d, 6H):

MS (+ve ESI): 664.3 (M+H)⁺.

di-tert-butyl 2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a)     2-(3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(3,5-difluorophenyl)acetamide     (2.0 g, 4.0 mmol) in 1-methyl-2-pyrrolidinone (20 ml), potassium     iodide (1.33 g, 8.0 mmol) was reacted with 2-(isobutylamino)ethanol     (1.88 g, 16 mmol) under argon, at 60° C. for 8 hours. The solvent     was evaporated in vacuo, and the residue was purified by     chromatography on silica gel, eluting with dichloromethane/methanol     (95:5) to dichloromethane/methanol/ammonia (7.0 N) (95:5:1) to yield     N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (1.05 g, 45% yield):

¹H-NMR (DMSO d₆, TFA): 8.95 (s, 1H), 8.29 (s, 1H), 7.35 (d, 2H), 7.34 (s, 1H), 6.92 (t, 1H), 6.83 (s, 1H), 4.30 (m, 2H), 4.00 (s, 3H), 3.86 (s, 2H), 3.82 (t, 2H), 3.89 (m, 2H), 3.29 (m, 2H), 2.17-2.98 (m, 2H), 2.30 (m, 2H), 2.13 (m, 1H), 1.01 (d, 6H):

MS (+ve ESI): 584.3 (M+H)⁺.

-   b) Di-tert-butyl-diethylphosphoramidite (1.25 ml, 4.18 mmol) was     slowly added to a solution of     N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (1.03 g, 1.73 mmol) in dimethylformamide (6 ml) in the presence of     tetrazole (431 mg, 6.16 mmol). The mixture was stirred at ambient     temperature for 2 hours before dichloromethane (30 ml) was added.     The resulting mixture was washed with a saturated solution of sodium     bicarbonate (15 ml), the aqueous phase was extracted with     dichloromethane (3×25 ml), dried and concentrated in vacuo. The     crude product was dissolved in tetrahydrofuran (25 ml), cooled to     0° C. and hydrogen peroxide (30% w/w, 0.40 ml, 3.9 mmol) was slowly     added to the solution. The reaction was stirred for 2 hours at     ambient temperature, cooled to 0° C., and treated with a solution of     sodium metabisulphite (1.08 g, 5.7 mmol) in water (2 ml). The     mixture was stirred for 0.5 hour at ambient temperature, diluted     with ethyl acetate (30 ml), washed with aqueous sodium bicarbonate     solution (15 ml) and extracted twice with ethyl acetate (20 ml)     Solvent evaporation in vacuo followed by purification by     chromatography on silica gel, eluting with dichloromethane/methanol     (98:2) to dichloromethane/methanol/ammonia (7.0 N) (95:5:1) yielded     di-tert-butyl     2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl     phosphate (335 mg, 25% yield):

¹H-NMR (DMSO d₆, TFA): 12.35 (s, 1H), 10.64 (s, 1H), 10.16 (s, 1H), 8.45 (s, 1H), 7.99 (s, 1H), 7.36 (d, 2H), 7.13 (s, 1H), 6.94 (t, 1H), 6.84 (s, 1H), 4.19 (t, 2H), 3.95 (s, 3H), 3.87 (q, 2H), 3.79 (s, 2H), 2.65 (m, 4H), 2.21 (d, 2H), 1.91 (m, 2H), 1.70 (m, 1H), 1.39 (s, 18H), 0.83 (d, 6H):

MS (+ve ESI): 776.4 (M+H)⁺.

EXAMPLE 9 Preparation of compound 9 in table 1—2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](propyl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1 but starting with di-tert-butyl 2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](propyl)amino]ethyl phosphate (510 mg, 0.67 mmol) yielded compound 9 in table 1 (503 mg, 42% yield):

¹H-NMR (DMSO (16, TFA): 8.94 (s, 1H), 8.31 (s, 1H), 7.38 (d, 1H), 7.37 (s, 2H), 7.36 (d, 1H), 6.92 (t, 1H), 6.83 (s, 1H), 4.30 (t, 2H), 4.24 (t, 2H), 4.00 (s, 3H), 3.87 (s, 2H), 3.49 (t, 2H), 3.36 (t, 2H), 3.18 (t, 2H), 2.26-2.36 (m, 2H), 1.68-1.79 (m, 2H), 0.94 (t, 3H):

MS (+ve ESI): 649.9 (M+H)⁺.

di-tert-butyl 2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](propyl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 8a, but     starting with 2-(propylamino)ethanol (1.83 ml, 16 mmol) yielded     N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (900 mg, 39% yield):

¹H-NMR (DMSO d₆): 10.63 (s, 1H), 10.17 (s, 1H), 8.46 (s, 1H), 8.00 (s, 1H), 7.36 (d, 2H), 7.14 (s, 1H), 6.94 (t, 1H), 6.85 (s, 1H), 4.35 (br s, 1H), 4.20 (t, 2H), 3.95 (s, 3H), 3.79 (s, 2H), 3.46 (m, 2H), 2.63 (m, 2H), 2.52 (m, 2H), 2.42 (m, 2H), 1.92 (m, 2H), 1.42 (m, 2H), 0.83 (t, 3H):

MS (+ve ESI): 570.3 (M+H)⁺.

-   b) An analogous reaction to that described in example 8b, but     starting with     N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (880 mg, 1.54 mmol) yielded di-tert-butyl     2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     phosphate (525 mg, 45% yield):

¹H-NMR (DMSO d₆, TFA): 12.35 (s, 1H), 10.63 (s, 1H), 10.16 (s, 1H), 8.45 (s, 1H), 7.99 (s, 1H), 7.37 (d, 1H), 7.34 (d, 1H), 7.13 (s, 1H), 6.94 (t, 1H), 6.84 (s, 1H), 4.17 (t, 2H), 3.94 (s, 3H), 3.87 (q, 2H), 3.79 (s, 2H), 2.67 (t, 2H), 2.63 (t, 2H), 2.43 (t, 2H), 1.91 (t, 2H), 1.39 (s, 18H), 0.83 (t, 3H):

MS (+ve ESI): 762.6 (M+H)⁺.

EXAMPLE 10 Preparation of compound 10 in table 1—2-[[3-({4[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl phosphate (450 mg, 0.59 mmol) yielded compound 10 in table 1 (420 mg, 99% yield):

¹H-NMR (DMSO d₆, TFA): 8.90 (s, 1H), 8.30 (s, 1H), 7.64 (m, 1H), 7.36 (m, 3H), 6.85 (m, 2H), 4.30 (m, 4H), 4.00 (s, 3H), 3.86 (s, 2H), 3.53 (m, 2H), 3.37 (m, 2H), 3.09 (m, 2H), 2.34 (m, 2H), 2.14 (m, 1H), 1.05 (m, 6H):

MS (+ve ESI): 646.6 (M+H)⁺.

di-tert-butyl 2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 5a, but     starting with 2-(isobutyl amino)ethanol (181 mg, 1.55 mmol) yielded     N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (101 mg, 57% yield):

¹H-NMR (DMSO d₆, TFA): 8.96 (s, 1H), 8.30 (s, 1H), 7.63 (d, 1H), 7.32-7.41 (m, 2H), 7.34 (s, 1H), 6.90 (t, 1H), 6.83 (s, 1H), 4.30 (t, 2H), 4.00 (s, 3H), 3.84 (s, 2H), 3.80 (t, 2H), 3.37 (t, 2H), 3.28 (t, 2H), 3.15-3.00 (m, 2H), 2.29 (m, 2H), 2.12 (m, 2H), 1.00 (d, 6H):

MS (+ve ESI): 566.3 (M+H)⁺.

-   b) An analogous reaction to that described in example 5b, but     starting with     N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (565 mg, 1 mmol) yielded di-tert-butyl     2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isobutyl)amino]ethyl     phosphate (420 mg, 55% yield):

¹H-NMR (DMSO d₆, TFA): 8.37 (s, 1H), 7.88 (s, 1H), 7.55 (m, 1H), 7.26 (m, 2H), 7.04 (s, 1H), 6.81 (m, 2H), 4.09 (t, 2H), 3.82 (s, 3H), 3.76 (m, 2H), 3.67 (m, 2H), 2.57 (m, 4H), 2.11 (m, 2H), 1.82 (m, 2H), 1.60 (m, 1H), 1.29 (s, 18H), 0.74 (d, 6H):

MS (+ve ESI): 758.5 (M+H)⁺.

EXAMPLE 11 Preparation of compound 11 in table 1—2-{(2,2-dimethylpropyl)[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-{(2,2-dimethylpropyl)[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl phosphate (350 mg, 0.45 mmol) yielded compound 11 in table 1 (325 mg, 100% yield):

¹H-NMR (DMSO d₆, TFA): 8.94 (s, 1H), 8.3 (s, 1H), 7.63 (d, 1H), 7.36 (s, 1H), 7.34 (m, 2H), 6.88 (m, 1H), 6.82 (s, 1H), 4.30 (m, 4H), 3.99 (s, 3H), 3.84 (s, 2H), 3.54 (m, 2H), 3.38 (m, 2H), 3.19 (m, 2H), 2.37 (m, 2H), 1.09 (s, 9H):

MS (+ve ESI): 660.4 (M+H)⁺.

di-tert-butyl 2-{(2,2-dimethylpropyl)[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl phosphate used as starting material was obtained as follows:

-   a) Ethylene oxide (2.5 ml, 5.0 mmol) cooled to −20° C. was slowly     added to a solution of (2,2-dimethylpropyl)amine (13 g, 150 mmol) in     methanol (15 ml) at −30° C. under argon. The mixture was stirred at     ambient temperature for 16 hours. The solvent was evaporated in     vacuo, and the residue was purified by distillation (b.p. 132° C./9     mmHg) to yield 2-((2,2-dimethylpropyl)amino)ethanol (6.4 g, 97%     yield):

¹H-NMR (DMSO d₆, TFA): 3.70 (m, 2H), 3.02 (m, 2H), 2.81 (m, 2H), 0.98 (s, 9H).

-   b) An analogous reaction to that described in example 5a, but     starting with 2-(2,2-dimethylpropyl)amino)ethanol (203 mg, 1.55     mmol) yielded     2-{3-[(7-{3-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide     (111 mg, 61% yield):

¹H-NMR (DMSO d₆, TFA): 8.96 (s, 1H), 8.30 (s, 1H), 7.64 (d, 1H), 7.32-7.41 (m, 2H), 7.34 (s, 1H), 6.90 (t, 1H), 6.83 (s, 1H), 4.31 (t, 2H), 3.99 (s, 3H), 3.84 (s, 2H), 3.83 (t, 2H), 3.42 (t, 2H), 3.32 (t, 2H), 3.20 (dd, 2H), 2.35 (m, 2H), 1.07 (s, 9H):

MS (+ve ESI): 580.3 (M+H)⁺.

-   c) An analogous reaction to that described in example 5b, but     starting with     2-{3-[(7-{3-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide     (1.33 g, 2.3 mmol) yielded di-tert-butyl     2-{(2,2-dimethylpropyl)[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     phosphate (620 mg, 40% yield):

¹H-NMR (DMSO d₆, TFA): 8.95 (s, 1H), 8.3 (s, 1H), 7.64 (d, 1H), 7.28-7.40 (m, 2H), 7.34 (s, 1H), 6.88 (m, 1H), 6.84 (s, 1H), 4.31 (m, 4H), 4.00 (s, 3H), 3.85 (s, 2H), 3.56 (m, 2H), 3.39 (m, 2H), 3.21 (m, 2H), 2.32 (m, 2H), 1.43 (s, 9H), 1.10 (s, 9H):

MS (+ve ESI): 716.4 (M+H)⁺.

EXAMPLE 12 Preparation of compound 12 in table 1—1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-3-yl dihydrogen phosphate

-   An analogous reaction to that described in example 1, but starting     with di-tert-butyl     1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-3-yl     phosphate (540 mg, 0.72 mmol) yielded compound 12 in table 1 (500     mg, 98% yield):

¹H-NMR (DMSO d₆, TFA): 8.92 (s, 1H), 8.28 (s, 1H), 7.62 (d, 1H), 7.32 (m, 3H), 6.82 (m, 2H), 4.45-4.66 (m, 2H), 4.27 (m, 2H), 3.99 (s, 3H), 3.84 (s, 2H), 3.55 (m, 2H), 3.30 (m, 2H), 3.00 (m, 2H), 2.30 (m, 2H), 2.05 (m, 2H), 1.65 (m, 2H):

MS (+ve ESI): 630.2 (M+H)⁺.

di-tert-butyl 1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-3-yl phosphate used starting material was obtained as follows:

-   a) An analogous reaction to that described in example 5a, but     starting with piperidin-3-ol (101 mg, 1 mmol) yielded     N-(3-fluorophenyl)-2-[3-({7-[3-(3-hydroxypiperidin-1-yl)propoxy]-6-methoxyquinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetamide     (65 mg, 47% yield):

¹H-NMR (DMSO d₆, TFA): 8.96 (s, 1H), 8.29 (s, 1H), 7.62 (d, 1H), 7.38 (m, 2H), 7.34 (m, 2H), 7.34 (s, 1H), 6.90 (m, 1H), 6.84 (s, 1H), 4.28 (m, 2H), 4.10 (m, 1H), 4.00 (s, 3H), 3.85 (s, 2H), 2.80-3.50 (m, 6H), 1.30-2.40 (m, 6H):

MS (+ve ESI): 550.6 (M+H)⁺.

-   b) An analogous reaction to that described in example 5b, but     starting with     N-(3-fluorophenyl)-2-[3-({7-[3-(3-hydroxypiperidin-1-yl)propoxy]-6-methoxyquinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetamide     (604 mg, 1.11 mmol) yielded di-tert-butyl     1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-3-yl     phosphate (550 mg, 67% yield):

¹H-NMR (DMSO d₆, TFA): 8.38 (s, 1H), 7.90 (s, 1H), 7.55 (d, 1H), 7.30 (m, 2H), 7.06 (s, 1H), 6.80 (m, 2H), 4.09 (m, 3H), 3.86 (s, 3H), 3.68 (s, 2H), 2.80 (m, 1H), 2.55 (m, 1H), 2.03 (m, 2H), 1.87 (m, 3H), 1.60 (m, 1H), 1.35 (m, 22H):

MS (+ve ESI): 742.5 (M+H)⁺.

EXAMPLE 13 Preparation of compound 13 in table 1—{(2R)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl {(2R)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl phosphate (445 mg, 0.59 mmol) yielded compound 13 in table 1 (440 mg, 94% yield):

¹H-NMR (DMSO d₆, TFA): 8.94 (s, 1H), 8.31 (s, 1H), 7.73 (m, 1H), 7.40 (s, 1H), 7.19 (m, 2H), 6.83 (s, 1H), 4.31 (t, 2H), 4.20 (m, 2H), 4.01 (s, 3H), 3.94 (s, 2H), 3.82 (m, 1H), 3.70 (m, 1H), 3.60 (m, 1H), 3.31 (m, 1H), 3.23 (m, 1H), 2.32 (m, 2H), 2.19 (m, 1H), 2.04 (m, 1H), 1.95 (m, 1H), 1.85 (m, 1H):

MS (+ve ESI): 648.3 (M+H)⁺.

di-tert-butyl {(2R)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 6b, but     starting with (2R)-pyrrolidin-2-ylmethanol (101 mg, 1 mmol) yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (134 mg, 79% yield):

¹H-NMR (DMSO d₆, TFA): 8.95 (s, 1H), 8.29 (s, 1H), 7.75 (m, 1H), 7.32 (s, 1H), 7.16 (m, 2H), 6.84 (s, 1H), 4.30 (m, 2H), 4.00 (s, 3H), 3.94 (s, 2H), 3.70-3.85 (m, 1H), 3.52-3.70 (m, 4H), 3.15-3.30 (m, 2H), 2.25-2.35 (m, 2H), 1.75-2.20 (m, 4H):

MS ES⁺: 568.2 (M+H)⁺

MS (+ve ESI): 568.2 (M+H)⁺.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (1.1 g, 1.9 mmol) yielded di-tert-butyl     {(2R)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     phosphate (453 mg, 31% yield):

¹H-NMR (DMSO d₆, TFA): 10.24 (s, 1H), 10.15 (s, 1H), 8.44 (s, 1H), 7.98 (s, 1H), 7.72 (t, 1H), 7.19 (m, 2H), 7.13 (s, 1H), 6.83 (s, 1H), 4.17 (br s, 2H), 3.93 (s, 3H), 3.85 (s, 1H), 3.77 (m, 1H), 3.56 (t, 1H), 3.54 (t, 1H), 3.08 (t, 1H), 2.94 (m, 1H), 2.66 (m, 1H), 2.47 (m, 1H), 2.20 (q, 1H), 1.94 (m, 2H), 1.86 (m, 1H), 1.69 (m, 2H), 1.60 (m, 1H), 1.37 (s, 9H), 1.36 (s, 9H):

MS (+ve ESI): 758.5 (M+H)⁺.

Compound 13, synthesised above as the dihydrochloride salt, could also be prepared as the free base according to the following method:

-   c) An analogous reaction to that described in example 6d, but     starting with Compound 13 yielded the free base of Compound 13 as a     pale yellow solid:

¹H-NMR (DMSO d₆): 10.30 (s, 1H), 10.20 (s, 1H), 8.50 (s, 1H), 8.00 (s, 1H), 7.70-7.80 (m, 1H), 7.20-7.30 (m, 3H), 6.70 (s, 1H), 4.30-4.40 (m, 2H), 4.10-4.20 (m, 1H), 3.90 (s, 3H), 3.80 (s, 2H), 3.70-3.75 (m, 1H), 3.40-3.50 (m, 1H), 3.30-3.35 (m, 1H), 3.20-3.25 (m, 1H), 3.05-3.15 (m, 1H), 2.90-3.00 (m, 1H), 2.10-2.20 (m, 2H), 1.90-2.00 (m, 1H), 1.70-1.80 (m, 3H):

MS (+ve ESI): 648 (M+H)⁺.

C₂₈H₃₂F₂N₇O₇P+2.3H₂O requires C, 48.8%; H, 5.35%; N, 14.23%; Found C, 48.95%; H, 5.03%; N, 14.15%

EXAMPLE 14 Preparation of compound 14 in table 1—2-[[3-({4-[(5-}2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl]oxy)propyl](prop-2-yn-1-yl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](prop-2-yn-1-yl)amino]ethyl phosphate (400 mg, 0.53 mmol) yielded compound 14 in table 1 (290 mg, 77% yield):

¹H-NMR (DMSO d₆, TFA): 8.94 (s, 1H), 8.34 (s, 1H), 7.42 (m, 3H), 6.89 (m, 2H), 4.37 (m, 6H), 4.04 (s, 3H), 3.92 (s, 2H), 3.87 (s, 1H), 3.57 (m, 2H), 3.47 (m, 2H), 2.39 (m, 2H):

MS (+ve ESI): 646.4 (M+H)⁺.

di-tert-butyl 2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](prop-2-yn-1-yl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a) A cooled (−40° C.) solution of ethylene oxide (3.3 g, 75 mmol) in     methanol (10 ml) was slowly added to a solution of propargylamine     (16.5 g, 300 mmol) in methanol (60 ml) cooled to −65° C. under     argon. The mixture was allowed to warm to ambient temperature over     16 hours, the solvent was evaporated in vacuo, and the residue was     purified by distillation to yield 2-(prop-2-yn-1-ylamino)ethanol     (5.0 g, 67% yield):

¹H-NMR (DMSO d₆, TFA): 3.91 (m, 2H), 3.65 (m, 3H), 3.06 (m, 2H).

-   b) An analogous reaction to that described in example 8a, but     starting with 2-(prop-2-yn-1-ylamino)ethanol (99 mg, 1 mmol) and     heating at 105° C. for 12 hours yielded     N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-1-yl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (50 mg, 31% yield):

¹H-NMR (DMSO d₆, TFA): 8.95 (s, 1H), 8.29 (s, 1H), 7.34 (m, 2H), 7.31 (s, 1H), 6.91 (m, 1H), 6.83 (s, 1H), 4.29 (m, 4H), 4.00 (s, 3H), 3.89 (m, 1H), 3.86 (s, 2H), 3.80 (m, 2H), 3.43 (m, 2H), 3.36 (m, 2H), 2.30 (m, 2H):

MS (+ve ESI): 566.2 (M+H)⁺.

-   c) An analogous reaction to that described in example 8b, but     starting with     N-(3,5-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-1-yl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (734 mg, 1.3 mmol) yielded di-tert-butyl     2-[[3-({4-[(5-{2-[(3,5-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](prop-2-yn-1-yl)amino]ethyl     phosphate (400 mg, 41% yield):

¹H-NMR (DMSO d₆, TFA): 8.51 (s, 1H), 7.99 (s, 1H), 7.35 (m, 2H), 7.28 (s, 1H), 6.93 (m, 1H), 6.72 (s, 1H), 4.21 (m, 2H), 3.95 (m, 5H), 3.75 (m, 2H), 3.60 (m, 2H), 3.28 (s, 1H), 2.85 (m, 2H), 2.79 (m, 2H), 1.97 (m, 2H), 1.37 (s, 9H).

EXAMPLE 15 Preparation of compound 15 in table 1—2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isopropyl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isopropyl)amino]ethyl phosphate (450 mg, 0.59 mmol) yielded compound 15 in table 1 (405 mg, 95% yield):

¹H-NMR (DMSO d₆): 8.90 (s, 1H), 8.32 (s, 1H), 7.69 (m, 1H), 7.51 (s, 1H), 7.21 (m, 2H), 6.81 (s, 1H), 4.33 (m, 2H), 4.26 (m, 2H), 4.00 (s, 3H), 3.92 (s, 2H), 3.72 (m, 1H), 3.40 (m, 2H), 3.29 (m, 2H), 2.32 (m, 2H), 1.31 (m, 6H):

MS (+ve ESI): 650.3 (M+H)⁺.

di-tert-butyl 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isopropyl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 6b, but     starting with 2-(isopropylamino)ethanol (103 mg, 1 mmol) yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isopropyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (84 mg, 49% yield):

¹H-NMR (DMSO d₆, TFA): 8.97 (s, 1H), 8.33 (s, 1H), 7.79 (m, 1H), 7.35 (s, 1H), 7.18 (m, 2H), 6.88 (s, 1H), 4.34 (t, 2H), 4.03 (s, 3H), 3.98 (s, 2H), 3.81 (m, 3H), 3.40 (m, 3H), 3.20 (m, 1H), 2.35 (m, 2H), 1.33 (m, 6H):

MS (+ve ESI): 570.2 (M+H)⁺.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(isopropyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (650 mg, 1.14 mmol) yielded di-tert-butyl     2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](isopropyl)amino]ethyl     phosphate (520 mg, 60% yield):

¹H-NMR (DMSO d₆): 8.44 (s, 1H), 7.98 (s, 1H), 7.73 (m, 1H), 7.19 (m, 2H), 7.12 (s, 1H), 6.83 (s, 1H), 4.16 (t, 2H), 3.93 (s, 3H), 3.85 (s, 2H), 3.77 (m, 2H), 2.90 (m, 1H), 2.60 (m, 4H), 1.86 (m, 2H), 1.36 (s, 18H), 0.94 (m, 6H):

MS (+ve ESI): 762.7 (M+H)⁺. EXAMPLE 16

Preparation of compound 16 in table 1—2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](prop-2-yn-1-yl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](prop-2-yn-1-yl)amino]ethyl phosphate (630 mg, 0.84 mmol) yielded compound 16 in table 1 ((540 mg, 86% yield):

¹H-NMR (DMSO d₆, AcOD): 8.89 (s, 1H), 8.29 (m, 1H), 7.70 (m, 1H), 7.37 (m, 1H), 7.16 (m, 2H), 6.81 (m, 1H), 4.29 (m, 6H), 3.99 (m, 3H), 3.92 (m, 2H), 3.82 (m, 1H), 3.52 (m, 2H), 3.43 (m, 2H), 2.32 (m, 2H):

MS (+ve ESI): 646.3 (M+H)⁺.

di-tert-butyl 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](prop-2-yn-1-yl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 6b, but     starting with 2-(prop-2-yn-1-ylamino)ethanol (99 mg, 1 mmol) yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-1-yl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (128 mg, 75% yield):

¹H-NMR (DMSO d₆, TFA): 8.95 (s, 1H), 8.29 (s, 1H), 7.74 (m, 1H), 7.31 (s, 1H), 7.18 (m, 2H), 6.83 (s, 1H), 4.30 (m, 4H), 4.00 (s, 3H), 3.94 (s, 2H), 3.87 (m, 1H), 3.80 (m, 2H), 3.44 (m, 2H), 3.35 (m, 2H), 2.30 (m, 2H):

MS (+ve ESI): 566.2 (M+H)⁺.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-1-yl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (680 mg, 1.2 mmol) yielded di-tert-butyl     2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](prop-2-yn-1-yl)amino]ethyl     phosphate (630 mg, 70% yield):

¹H-NMR (DMSO d₆): 8.45 (s, 1H), 7.98 (s, 1H), 7.72 (m, 1H), 7.17 (m, 3H), 6.83 (s, 1H), 4.16 (m, 2H), 3.85 (m, 7H), 3.45 (m, 2H), 3.13 (m, 1H), 2.69 (m, 4H), 1.90 (m, 2H), 1.35 (m, 18H):

MS (+ve ESI): 758.5 (M+H)⁺.

EXAMPLE 17 Preparation of compound 17 in table 1—2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-Pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl]oxy)propyl](2-methoxyethyl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](2-methoxyethyl)amino]ethyl phosphate (500 mg, 0.64 mmol) yielded compound 17 in table 1 (450 mg, 94% yield):

¹H-NMR (DMSO d₆, AcOD): 8.91 (s, 1H), 8.33 (s, 1H), 7.74 (m, 1H), 7.43 (s, 1H), 7.18 (m, 2H), 6.85 (s, 1H), 4.32 (m, 4H), 4.02 (s, 3H), 3.96 (s, 2H), 3.77 (m, 2H), 3.56 (m, 2H), 3.49 (m, 2H), 3.44 (m, 2H), 3.34 (s, 3H), 2.34 (m, 2H):

MS (+ve ESI): 666.2 (M+H)⁺.

di-tert-butyl 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](2-methoxyethyl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 6b, but     starting with 2-((2-methoxyethyl)amino)ethanol (119 mg, 1     mmol—prepared according to A. A. Santilli et al, J. Heterocycl.     Chem. 1972, 9, 309-13) yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(2-methoxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (124 mg, 71% yield):

¹H-NMR (DMSO d₆, TFA): 8.97 (s, 1H), 8.31 (s, 1H), 7.76 (m, 1H), 7.33 (s, 1H), 7.19 (m, 2H), 6.85 (s, 1H), 4.31 (t, 2H), 4.02 (s, 3H), 3.95 (s, 2H), 3.80 (t, 2H), 3.73 (t, 2H), 3.45 (m, 4H), 3.36 (m, 5H), 2.31 (m, 2H):

MS (+ve ESI): 586.2 (M+H)⁺.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(2-methoxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (800 mg, 1.4 mmol) yielded di-tert-butyl     2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](2-methoxyethyl)amino]ethyl     phosphate (560 mg, 53% yield):

¹H-NMR (DMSO d₆): 8.44 (s, 1H), 7.99 (s, 1H), 7.72 (m, 1H), 7.20 (m, 2H), 7.12 (s, 1H), 6.84 (s, 1H), 4.16 (t, 2H), 3.93 (t, 3H), 3.85 (m, 4H), 3.38 (m, 2H), 3.20 (s, 3H), 2.74 (m, 2H), 2.67 (m, 4H), 1.90 (m, 2H), 1.39 (m, 18H):

MS (+ve ESI): 778.6 (M+H)⁺.

EXAMPLE 18 Preparation of compound 18 in table 1—2-{[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-{[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl phosphate (729 mg, 1.04 mmol) yielded compound 18 in table 1 (505 mg, 72% yield):

¹H-NMR (DMSO d₆, AcOD): 8.85 (s, 1H), 8.25 (s, 1H), 7.60 (d, 1H), 7.33 (m, 3H), 6.83 (m, 1H), 6.80 (s, 1H), 4.27 (m, 2H), 4.15 (m, 2H), 3.97 (s, 3H), 3.83 (s, 2H), 3.26 (m, 2H), 3.15 (m, 2H), 2.24 (m, 2H):

MS (+ve ESI): 590.1 (M+H)⁺.

di-tert-butyl 2-{[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 5a, but     starting with 2-(cyclopropylamino)ethanol (156 mg, 1.55 mmol)     yielded     2-{3-[(7-{3-[cyclopropyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide     (22 mg, 13% yield):

¹H-NMR (DMSO d₆, TFA): 8.97 (s, 1H), 8.31 (s, 1H), 7.65 (d, 1H), 7.33-7.42 (m, 2H), 7.37 (s, 1H), 6.92 (t, 1H), 6.85 (s, 1H), 4.33 (m, 2H), 4.02 (s, 3H), 3.86 (s, 2H), 3.79 (t, 2H), 3.48 (m, 2H), 3.42 (t, 2H), 2.97 (m, 1H), 2.36 (m, 2H), 1.04 (m, 2H), 0.94 (m, 2H): MS (+ve ESI): 550.2 (M+H)⁺.

-   b) An analogous reaction to that described in example 5b, but     starting with     2-{3-[(7-{3-[cyclopropyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide     (1.1 g, 2.0 mmol) yielded a mixture of di-tert-butyl     2-{cyclopropyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     phosphate (150 mg, 10% yield) together with di-tert-butyl     2-{[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     phosphate (730 mg, 52% yield) which was used in the next step:

¹H-NMR (DMSO d₆, TFA): 8.97 (s, 1H), 8.32 (s, 1H), 7.78 (d, 1H), 7.36 (m, 2H), 7.34 (s, 1H), 6.87 (m, 2H), 4.33 (m, 2H), 4.16 (m, 2H), 4.03 (s, 3H), 3.88 (s, 2H), 3.33 (m, 2H), 3.24 (m, 2H), 2.38 (m, 2H), 1.47 (s, 18H):

MS (+ve ESI): 702.5 (M+H)⁺.

EXAMPLE 19 Preparation of compound 19 in table 1—2-{(cyclobutylmethyl)[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl)-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-{(cyclobutylmethyl)[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl phosphate (400 mg, 0.508 mmol) yielded compound 19 in table 1 (365 mg, 96% yield):

¹H-NMR (DMSO d₆, AcOD): 8.92 (s, 1H), 8.33 (s, 1H), 7.71 (m, 1H), 7.44 (s, 1H), 7.19 (m, 2H), 6.82 (s, 1H), 4.30 (m, 4H), 4.00 (s, 3H), 3.94 (s, 2H), 3.42 (m, 2H), 3.29 (m, 4H), 2.82 (m, 1H), 2.31 (m, 2H), 2.13 (m, 2H), 1.87 (m, 4H):

MS (+ve ESI): 676.4 (M+H)⁺.

di-tert-butyl 2-{(cyclobutylmethyl)[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl phosphate used as starting material was obtained as follows:

-   a) Cyclobutane carbonyl chloride (5 ml, 43.8 mmol) was slowly added     to a solution of ethyl glycinate (5.86 g, 42 mmol) in     dichloromethane (100 ml) and triethylamine (14.6 ml, 105 mmol) at     0° C. The mixture was then stirred at ambient temperature for 14     hours. The reaction mixture was washed with a dilute hydrochloric     acid (1.0 N), the organic phase was separated, dried and evaporated     in vacuo to give a yellow solid. Recrystallisation from     dichloromethane/petroleum ether yielded ethyl     N-(cyclobutylcarbonyl)glycinate as a white solid (7.78 g, 100%     yield):

¹H-NMR (DMSO d₆): 8.08 (t, 1H), 4.09 (q, 2H), 3.79 (s, 2H), 3.07 (m, 1H), 2.00-2.18 (m, 4H), 1.89 (m, 1H), 1.78 (m, 1H), 1.20 (t, 3H).

-   b) Ethyl N-(cyclobutylcarbonyl)glycinate (7.6 g, 41 mmol) in     tetrahydrofuran (40 ml) was added to a solution of diborane (100 ml     of a 1.0 N solution in tetrahydrofuran, 100 mmol) and heated at     60° C. for 24 hours. Additional diborane (20 ml of a 1.0 N solution     in tetrahydrofuran, 20 mmol) was added to the mixture and heating     was carried out for a further 8 hours. Methanol (20 ml) was added     cautiously and the reaction stirred for 30 minutes at ambient     temperature before slow addition of hydrochloric acid (6 ml of a 6.0     N solution). The reaction was concentrated in vacuo, dichloromethane     was added and the solid material removed by suction filtration. The     organic filtrate was dried, concentrated in vacuo and purified by     chromatography on silica gel, eluting with dichloromethane/methanol     (96:4) to dichloromethane/methanol/ammonia (7.0N) (94:5:1) to yield     2-((cyclobutylmethyl)amino)ethanol (4.16 g, 78% yield):

¹H-NMR (DMSO d₆, TFA): 8.38 (br s, 1H), 3.65 (t, 2H), 2.98 (m, 4H), 2.62 (m, 2H), 2.06 (m, 2H), 1.72-1.94 (m, 4H).

-   c) An analogous reaction to that described in example 6b, but     starting with 2-((cyclobutylmethyl)amino)ethanol (129 mg, 1 mmol)     yielded     2-{3-[(7-{3-[(cyclobutylmethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide     (134 mg, 75% yield):

¹H-NMR (DMSO d₆): 8.49 (s, 1H), 8.00 (s, 1H), 7.74 (m, 1H), 7.15-7.30 (m, 3H), 6.75 (m, 1H), 4.25 (m, 2H), 3.96 (s, 3H), 3.86 (s, 2H), 3.60-3.80 (m, 2H), 3.30-3.40 (m, 4H), 2.50-2.80 (m, 4H), 1.60-2.40 (m, 7H):

MS (+ve ESI): 596.2 (M+H)⁺.

-   d) An analogous reaction to that described in example 6c, but     starting with     2-{3-[(7-{3-[(cyclobutylmethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide     (773 mg, 1.3 mmol) yielded di-tert-butyl     2-{(cyclobutylmethyl)[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     phosphate (400 mg, 40% yield):

¹H-NMR (DMSO d₆): 8.45 (s, 1H), 7.99 (s, 1H), 7.72 (m, 1H), 7.20 (m, 3H), 6.83 (s, 1H), 4.15 (s, 2H), 3.94 (s, 3H), 3.85 (m, 4H), 2.60 (m, 4H), 2.47 (m, 3H), 1.88 (m, 4H), 1.75 (m, 2H), 1.60 (m, 2H), 1.36 (s, 18H):

MS (+ve ESI): 788.8 (M+H)⁺.

EXAMPLE 20 Preparation of compound 20 in table 1—2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](3,3,3-trifluoropropyl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](3,3,3-trifluoropropyl)amino]ethyl phosphate (450 mg, 0.56 mmol) yielded compound 20 in table 1 (405 mg, 46% yield):

¹H-NMR (DMSO d₆, TFA): 8.95 (s, 1H), 8.32 (s, 1H), 7.65 (d, 1H), 7.39 (s, 1H), 7.36 (m, 1H), 6.89 (m, 1H), 6.83 (s, 1H), 4.31 (t, 2H), 4.27 (m, 2H), 4.01 (s, 2H), 3.86 (s, 2H), 3.57 (br s, 2H), 3.54 (m, 2H), 3.43 (t, 2H), 2.97 (m, 2H), 2.33 (m, 2H):

MS (+ve ESI): 686.4 (M+H)⁺.

di-tert-butyl 2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](3,3,3-trifluoropropyl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a) A solution of 3-bromo-1,1,1-trifluoropropane (5.5 ml, 51.6 mmol)     in dioxane (50 ml) was heated with ethanol amine (3 ml, 51.25 mmol)     at 60° C. for 36 hours in the presence of potassium carbonate (14.2     g, 102 mmol). The solvent was evaporated in vacuo and the residue     was purified by chromatography on silica gel, eluting with     dichloromethane/methanol (95:5) to dichloromethane/methanol/ammonia     (7.0 N) (95:5:1) to yield 2-((3,3,3-trifluoropropyl)amino)ethanol     (4.47 g, 55% yield):

¹H-NMR (DMSO d₆, TFA): 3.56 (t, 2H), 2.97 (t, 2H), 2.82 (t, 2H), 2.57 (m, 2H).

-   b) An analogous reaction to that described in example 5a, but     starting with 2-((3,3,3-trifluoropropyl)amino)ethanol (221 mg, 1.55     mmol) yielded     N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(3,3,3-trifluoropropyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (77 mg, 41% yield):

¹H-NMR (DMSO d₆, TFA): 8.96 (s, 1H), 8.29 (s, 1H), 7.63 (d, 1H), 7.31-7.40 (m, 2H), 7.33 (s, 1H), 6.89 (t, 1H), 6.83 (s, 1H), 4.29 (t, 2H), 3.99 (s, 3H), 3.84 (s, 2H), 3.79 (t, 2H), 3.51 (m, 2H), 3.38 (m, 2H), 2.91 (m, 2H), 2.29 (m, 2H):

MS (+ve ESI): 606.2 (M+H)⁺.

-   c) An analogous reaction to that described in example 5b, but     starting with     N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(3,3,3-trifluoropropyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (651 mg, 1.07 mmol) yielded di-tert-butyl     2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl](3,3,3-trifluoropropyl)amino]ethyl     phosphate (455 mg, 53% yield):

¹H-NMR (DMSO d₆): 10.45 (s, 1H), 10.15 (s, 1H), 8.44 (s, 1H), 7.98 (s, 1H), 7.62 (d, 1H), 7.35 (m, 1H), 7.33 (s, 1H), 7.13 (s, 1H), 6.89 (t, 1H), 6.82 (s, 1H), 4.16 (t, 2H), 3.93 (s, 3H), 3.87 (q, 2H), 3.76 (s, 2H), 2.73 (m, 4H), 2.66 (t, 2H), 2.42 (m, 2H), 1.90 (m, 2H), 1.37 (s, 18H):

MS (+ve ESI): 797.9 (M+H)⁺.

EXAMPLE 21 Preparation of compound 21 in table 1—2-{allyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with 2-{allyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl di-tert-butyl phosphate (310 mg, 0.408 mmol) yielded compound 21 in table 1 (293 mg, 100% yield):

¹H-NMR (DMSO d₆, AcOD): 8.92 (s, 1H), 8.32 (s, 1H), 7.70 (m, 1H), 7.43 (s, 1H), 7.19 (m, 2H), 6.82 (s, 1H), 6.05 (m, 1H), 5.63 (m, 1H), 5.56 (m, 1H), 4.30 (m, 4H), 4.00 (s, 3H), 3.93 (m, 4H), 3.45 (m, 2H), 3.33 (m, 2H), 2.33 (m, 2H):

MS (+ve ESI): 648.3 (M+H)⁺.

2-{allyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl)amino}ethyl di-tert-butyl phosphate used as starting material was obtained as follows:

-   a) Ethylene oxide (2.5 ml, 50 mmol—cooled to −20° C.) was added to a     solution of allylamine (14 g, 250 mmol) in methanol (20 ml) at     −20° C. The mixture was stirred at ambient temperature for 14 hours,     the solvent was evaporated in vacuo and the residual oil was     purified by distillation (b.p. 140° C./14 mmHg) to yield     2-(allylamino)ethanol (4.2 g, 84% yield):

¹H-NMR (DMSO d₆): 5.83 (m, 1H), 5.14 (m, 1H), 5.02 (m, 1H), 3.43 (m, 2H), 3.14 (m, 2H), 2.50 (m, 2H).

-   b) An analogous reaction to that described in example 6b, but     starting with 2-(allylamino)ethanol (101 mg, 1 mmol) yielded     2-{3-[(7-{3-[allyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide     (99 mg, 58% yield):

¹H-NMR (DMSO d₆, TFA): 8.97 (s, 1H), 8.32 (s, 1H), 7.77 (m, 1H), 7.33 (s, 1H), 7.18 (m, 2H), 6.87 (s, 1H), 6.01 (m, 1H), 5.60 (m, 2H), 4.31 (t, 2H), 4.02 (s, 3H), 3.94 (m, 4H), 3.82 (t, 2H), 3.35 (m, 4H), 2.34 (m, 2H):

MS (+ve ESI): 568.2 (M+H)⁺.

-   c) An analogous reaction to that described in example 6c, but     starting with     2-{3-[(7-{3-[allyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide     (1.0 g, 1.76 mmol) yielded     2-{allyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl]oxy)propyl]amino}ethyl     di-tert-butyl phosphate (310 mg, 23% yield):

¹H-NMR (DMSO d₆, TFA): 8.97 (s, 1H), 8.30 (s, 1H), 7.75 (m, 1H), 7.32 (s, 1H), 7.20 (m, 2H), 6.85 (s, 1H), 6.00 (m, 1H), 5.74 (m, 2H), 4.30 (m, 4H), 4.01 (s, 3H), 3.95 (m, 4H), 3.50 (m, 2H), 3.37 (m, 2H), 2.30 (m, 2H), 1.45 (s, 18H):

MS (+ve ESI): 760.5 (M+H)⁺.

EXAMPLE 22 Preparation of compound 22 in table 1—2-{cyclobutyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}1-H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-{cyclobutyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl phosphate (450 mg, 0.58 mmol) yielded compound 22 in table 1 (420 mg, 98% yield):

¹H-NMR (DMSO d₆, AcOD): 8.91 (s, 1H), 8.31 (s, 1H), 7.72 (m, 1H), 7.42 (s, 1H), 7.20 (m, 2H), 6.82 (s, 1H), 4.28 (m, 4H), 4.00 (s, 3H), 3.94 (s, 3H), 3.35 (m, 2H), 3.25 (m, 2H), 2.41 (m, 2H), 2.25 (m, 4H), 1.70 (m, 2H):

MS (+ve ESI): 662.5 (M+H)⁺.

di-tert-butyl 2-{cyclobutyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 6b, but     starting with 2-(cyclobutylamino)ethanol (117 mg, 1 mmol—prepared     according to D. F. Morrow et al, J. Med. Chem. 1973, 16, 736-9.) and     potassium iodide (103 mg, 0.62 mmol) in dimethylacetamide (2 ml) at     95° C. for 4 hours under argon yielded     2-{3-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide     (97 mg, 56% yield):

¹H-NMR (DMSO d₆, TFA): 8.92 (s, 1H), 8.27 (s, 1H), 7.74 (m, 1H), 7.29 (s, 1H), 7.15-7.20 (m, 2H), 6.83 (s, 1H), 4.30 (m, 2H), 3.98 (s, 3H), 3.98 (m, 3H), 3.68-3.80 (m, 2H), 3.20-3.30 (m, 2H), 3.15 (m, 2H), 2.30 (m, 2H), 2.22 (m, 4H), 1.65-1.82 (m, 2H):

MS (+ve ESI): 582.2 (M+H)⁺.

-   b) An analogous reaction to that described in example 6c, but     starting with     2-{3-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide     (668 mg, 1.15 mmol) yielded di-tert-butyl     2-{cyclobutyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     phosphate (450 mg, 51% yield):

¹H-NMR (DMSO d₆): 8.44 (s, 1H), 7.98 (s, 1H), 7.70 (m, 1H), 7.18 (m, 3H), 6.83 (s, 1H), 4.15 (t, 2H), 3.90 (s, 3H), 3.85 (m, 4H), 3.15 (m, 1H), 2.62 (m, 4H), 1.90 (m, 4H), 1.75 (m, 2H), 1.53 (m, 2H), 1.39 (s, 18H):

MS (+ve ESI): 774.8 (M+H)⁺.

EXAMPLE 23 Preparation of compound 23 in table 1—2-{cyclopentyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-{cyclopentyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl phosphate (360 mg, 0.46 mmol) yielded compound 23 in table 1 (330 mg, 95% yield):

¹H-NMR (DMSO d₆, AcOD): 8.91 (s, 1H), 8.32 (s, 1H), 7.70 (m, 1H), 7.43 (s, 1H), 7.20 (m, 2H), 6.82 (s, 1H), 4.31 (m, 4H), 4.00 (s, 3H), 3.94 (s, 2H), 3.80 (m, 1H), 3.48 (m, 2H), 3.36 (m, 2H), 2.33 (m, 2H), 2.08 (m, 2H), 1.75 (m, 4H), 1.58 (m, 2H):

MS (+ve ESI): 676.5 (M+H)⁺.

di-tert-butyl 2-{cyclopentyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 6b, but     starting with 2-(cyclopentylamino)ethanol (129 mg, 1 mmol-prepared     according to D. F. Morrow et al. J. Med. Chem. 1973,16,736-9.)     yielded     2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide     (86 mg, 48% yield):

¹H-NMR (DMSO d₆, TFA): 8.93 (s, 1H), 8.28 (s, 1H), 7.73 (m, 1H), 7.30 (s, 1H), 7.14 (m, 2H), 6.83 (s, 1H), 4.29 (m, 2H), 3.98 (s, 3H), 3.93 (s, 2H), 3.78 (m, 3H), 3.37 (m, 2H), 3.26 (m, 2H), 2.30 (m, 2H), 2.09 (m, 2H), 1.74 (m, 4H), 1.72 (m, 2H):

MS (+ve ESI): 596.2 (M+H)⁺.

-   b) An analogous reaction to that described in example 6c, but     starting with     2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide     (654 mg, 1.1 mmol) yielded di-tert-butyl     2-{cyclopentyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     phosphate (364 mg, 42% yield):

¹H-NMR (DMSO d₆): 8.44 (s, 1H), 7.99 (s, 1H), 7.70 (m, 1H), 7.18 (m, 3H), 6.83 (s, 1H), 4.15 (m, 2H), 3.90 (s, 3H), 3.83 (m, 4H), 3.07 (m, 1H), 2.68 (m, 4H), 1.90 (m, 2H), 1.72 (m, 2H), 1.55 (m, 2H), 1.48 (m, 2H), 1.35 (m, 20H):

MS (+ve ESI): 789.0 (M+H)⁺.

EXAMPLE 24 Preparation of compound 24 in table 1—2-{cyclopropyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl dihydrogen phosphate

Hydrochloric acid (1.05 ml of a 4.0 N solution in dioxane, 4.2 mmol) was added to a stirred suspension of di-tert-butyl 2-{cyclopropyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl phosphate (519 mg, 0.7 mmol) in dichloromethane (15 ml) and dioxane (30 ml) and the reaction stirred for 7 hours at 45° C. The precipitate was recovered by suction filtration, the residue taken up in dichloromethane/methanol (8:2) and the solid material removed by filtration. The organic filtrate was evaporated in vacuo and the residue triturated with diethyl ether to yield compound 24 in table 1 (430 mg, 88% yield):

¹H-NMR (DMSO d₆, ACOH): 8.91 (s, 1H), 8.32 (s, 1H), 7.64 (m, 1H), 7.39 (m, 3H), 6.90 (m, 1H), 6.80 (s, 1H), 4.32 (m, 4H), 4.00 (s, 3H), 3.87 (s, 2H), 3.57 (m, 2H), 3.48 (m, 2H), 2.95 (m, 1H), 2.40 (m, 2H), 1.18 (m, 2H), 0.92 (m, 2H):

MS (+ve ESI): 630.4 (M+H)⁺.

di-tert-butyl 2-{cyclopropyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl phosphate used as starting material was obtained as follows:

-   a) Di-tert-butyl-diethylphosphoramidite (523 μl, 2.1 mmol) was added     within 5 minutes to a solution of     2-{3-[(7-{3-[cyclopropyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide     (793 mg, 1.4 mmol) in dimethylformamide (8 ml) in the presence of     tetrazole (245 mg, 3.5 mmol) at ambient temperature under argon and     the mixture was stirred for 1.5 hours. The solution was cooled to 5°     C., cumene hydroperoxide (426 mg, 2.8 mmol) was slowly added, and     the mixture stirred at 50° C. for 1 hour and at ambient temperature     for a further 1 hour. The mixture was cooled to 5° C. and triethyl     phosphite (415 mg, 2.5 mmol) was added and the reaction stirred at     ambient temperature for 1 hour. The solution was diluted with water,     extracted with ethyl acetate and the organic phase was separated,     dried and concentrated. The resultant oil was purified by     chromatography on silica gel, eluting with dichloromethane/methanol     (98:2) to dichloromethane/methanol/ammonia (7.0 N) (95:5:1), to give     di-tert-butyl     2-{cyclopropyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     phosphate as an off-white solid (630 mg, 59% yield):

¹H-NMR (DMSO d₆, TFA): 8.97 (s, 1H), 8.32 (s, 1H), 7.65 (d, 1H), 7.35 (m, 3H), 6.86 (m, 2H), 4.33 (m, 4H), 4.03 (s, 3H), 3.87 (s, 2H), 3.66 (m, 2H), 3.53 (m, 2H), 3.00 (m, 1H), 2.38 (m, 2H), 1.45 (s, 18H), 1.07 (m, 2H), 0.96 (m, 2H):

MS (+ve ESI): 759.7 (M+H)⁺.

EXAMPLE 25 Preparation of compound 25 in table 1—2-[(cyclopropylmethyl)[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-{(cyclopropylmethyl)[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl phosphate (725 mg, 0.94 mmol) yielded compound 25 in table 1 (661 mg, 90% yield):

¹H-NMR (DMSO d₆, TFA): 8.95 (s, 1H), 8.32 (s, 1H), 7.74 (m, 1H), 7.39 (s, 1H), 7.21 (m, 2H), 6.84 (s, 1H), 4.32 (t, 2H), 4.28 (m, 2H), 4.01 (s, 3H), 3.95 (s, 2H), 3.56 (br s, 2H), 3.46 (t, 2H), 3.19 (d, 2H), 2.32 (m, 2H), 1.18 (m, 1H), 0.68 (m, 2H), 0.47 (m, 2H):

MS (+ve ESI): 662.4 (M+H)⁺.

di-tert-butyl 2-{(cyclopropylmethyl)[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl phosphate used as starting material was obtained as follows:

-   a) Ethylchloroformate (4.2 ml, 37 mmol) was added to a stirred     solution of cyclopropylmethylamine (3.00 ml, 34.6 mmol) and     triethylamine (7 ml) in dichloromethane (35 ml) at 0° C. over 30     minutes. The reaction was stirred at ambient temperature for 2     hours, water (20 ml) was added to the mixture, and the pH adjusted     to 3 by addition of 2.0 N hydrochloric acid. The organic phase was     separated, dried and concentrated in vacuo to yield ethyl     (cyclopropylmethyl) carbamate (5.9 g, 100% yield):

¹H-NMR (CDCl₃): 7.24 (br s, 1H), 3.24 (m, 2H), 1.43 (t, 3H), 1.04 (m, 1H), 0.59 (m, 2H), 0.29 (m, 2H):

MS (+ve ESI): 172 (M+H)⁺.

-   b) A solution of ethyl (cyclopropylmethyl) carbamate (5.90 g, 34.6     mmol) in tetrahydrofuran (30 ml) was added at ambient temperature to     a solution of diborane (130 ml of a 1.0 N solution in     tetrahydrofuran, 130 mmol) and chlorotrimethylsilane (34 ml, 268     mmol) and the mixture stirred at ambient temperature for 48 hours.     Methanol (20 ml) was added and the reaction stirred for 30 minutes     at ambient temperature. Dichloromethane (25 ml) was added, followed     by hydrochloric acid (4 ml of a 6.0 N solution, 24 mmol) and the     reaction was stirred at ambient temperature for 30 minutes.     Methanolic ammonia (7.0 N) was added, the white solid was collected     by suction filtration and the organic filtrate was evaporated in     vacuo. Purification by chromatography on silica gel, eluting with     dichloromethane to dichloromethane/methanol (95:5) to     dichloromethane/methanol/ammonia (7.0 N) (90:9:1), yielded     2-((cyclopropylmethyl)amino)ethanol as a pale yellow liquid (2.99 g,     75% yield):

¹H-NMR (DMSO d₆, TFA): 3.66 (t, 2H), 3.02 (t, 2H), 2.84 (d, 2H), 1.06 (m, 1H), 0.58 (m, 2H), 0.35 (m, 2H).

-   c) An analogous reaction to that described in example 6b, but     starting with 2-(cyclopropylmethyl)amino)ethanol (115 mg, 1 mmol)     yielded     2-{3-[(7-{3-[(cyclopropylmethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide     (6 mg, 3% yield):

¹H-NMR (DMSO d₆): 10.23 (s, 1H), 10.16 (s, 1H), 8.44 (s, 1H), 7.98 (s, 1H), 7.72 (m, 1H), 7.18 (m, 2H), 7.14 (s, 1H), 6.84 (s, 1H), 4.32 (s, 1H), 4.18 (t, 2H), 3.93 (s, 3H), 3.85 (s, 2H), 3.45 (m, 2H), 2.69 (t, 2H), 2.58 (t, 2H), 2.35 (d, 2H), 1.90 (m, 2H), 0.83 (m, 1H), 0.41 (m, 2H), 0.08 (m, 2H):

MS (+ve ESI): 582.2 (M+H)⁺.

-   d) An analogous reaction to that described in example 6c, but     starting with     2-{3-[(7-{3-[(cyclopropylmethyl)(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide     (673 mg, 1.16 mmol) yielded di-tert-butyl     2-{(cyclopropylmethyl)[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     phosphate (110 mg, 12% yield):

¹H-NMR (DMSO d₆): 10.23 (s, 1H), 10.15 (s, 1H), 8.44 (s, 1H), 7.98 (s, 1H), 7.72 (t, 1H), 7.19 (m 2H), 7.13 (s, 1H), 6.83 (s, 1H), 4.17 (t, 2H), 3.93 (s, 3H), 3.88 (q, 2H), 3.85 (s, 2H), 2.76 (t, 2H), 2.72 (t, 2H), 2.38 (d, 2H), 1.91 (m, 2H), 1.37 (s, 18H), 0.83 (m, 1H), 0.42 (m, 2H), 0.09 (m, 2H):

MS (+ve ESI):774.7 (M+H)⁺.

EXAMPLE 26 Preparation of Compound 26 in Table 1—2-{cyclobutyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-{cyclobutyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl phosphate (416 mg, 0.55 mmol) yielded compound 26 in table 1 (455 mg, 100% yield):

¹H-NMR (DMSO d₆, TFA): 8.94 (s, 1H), 8.31 (s, 1H), 7.65 (d, 1H), 7.38 (m, 2H), 7.36 (s, 1H), 6.90 (m, 1H), 6.83 (s, 1H), 4.30 (t, 2H), 4.22 (m, 2H), 4.01 (s, 3H), 3.94 (m, 1H), 3.86 (s, 2H), 3.37 (s, 2H), 3.27 (br s, 2H), 2.35 (t, 2H), 2.26 (m, 4H), 1.77 (m, 1H), 1.68 (m, 1H):

MS (+ve ESI):644.2 (M+H)⁺.

di-tert-butyl 2-{cyclobutyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 5a, but     starting with 2-(cyclobutylamino)ethanol (178 mg, 1.55 mmol) yielded     2-{3-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide     (42 mg, 24% yield):

¹H-NMR (DMSO d₆, TFA): 8.96 (s, 1H), 8.29 (s, 1H), 7.64 (d, 1H), 7.36 (m, 2H), 7.34 (s, 1H), 6.90 (t, 1H), 6.83 (s, 1H), 4.29 (t, 2H), 4.00 (s, 3H), 3.94 (m, 1H), 3.85 (s, 2H), 3.75 (m, 2H), 3.25 (m, 2H), 3.17 (m, 2H), 2.08-2.39 (m, 6H), 1.76 (m, 1H), 1.69 (m, 1H):

MS (+ve ESI):564.2 (M+H)⁺.

-   b) An analogous reaction to that described in example 5b, but     starting with     2-{3-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide     (474 mg, 0.84 mmol) yielded di-tert-butyl     2-{cyclobutyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]amino}ethyl     phosphate (109 mg, 17% yield):

¹H-NMR (DMSO d₆): 10.46 (s, 1H), 10.16 (s, 1H), 8.44 (s, 1H), 7.98 (s, 1H), 7.62 (d, 1H), 7.34 (m, 1H), 7.33 (s, 1H), 7.13 (s, 1H), 6.89 (t, 1H), 6.82 (s, 1H), 4.15 (t, 2H), 3.93 (s, 3H), 3.84 (q, 2H), 3.76 (s, 2H), 3.16 (m, 1H), 2.64 (t, 2H), 2.59 (t, 2H), 1.96 (m, 2H), 1.88 (m, 2H), 1.77 (m, 2H), 1.55 (m, 2H), 1.38 (s, 18H):

MS (+ve ESI):756.7 (M+H)⁺.

EXAMPLE 27 Preparation of Compound 27 in Table 2—2-{4-[({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-{4-[({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyl phosphate (230 mg, 0.32 mmol) yielded compound 27 in table 2 (230 mg, 95% yield) as a white solid:

¹H-NMR (DMSO d₆): 12.00 (s, 1H), 10.40 (s, 1H), 8.95 (s, 1H), 8.80 (d, 1H), 7.70-7.80 (m, 1H), 7.40 (d, 1H), 7.35 (s, 1H), 7.15-7.25 (m, 2H), 6.70 (s, 1H), 4.20-4.30 (m, 2H), 4.05-4.15 (m, 2H), 3.90 (s, 2H), 3.50-3.60 (m, 2H), 3.10-3.25 (m, 2H), 2.27 (m, 1H), 2.10-2.20 (m, 2H), 1.70-1.90 (m, 2H), 1.20 (t, 2H):

MS (+ve ESI):618 (M+H)⁺,

MS (−ve ESI):616 (M−H)⁻.

di-tert-butyl 2-{4-[({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyl phosphate used as starting material was obtained as follows:

-   a) Dimethylformamide (0.1 ml) was added to a stirred suspension of     7-(benzyloxy)quinazolin-4(3H)-one (4.00 g, 15.9 mmol) in thionyl     chloride (25 ml) and the reaction heated at 85° C. for 1 hour. The     reaction was cooled, the excess thionyl chloride was evaporated in     vacuo and the residue was azeotroped with toluene (2×25 ml) before     being taken up in dimethylacetamide (20 ml).     5-amino-1H-pyrazol-3-ylacetic acid (2.27 g, 15.9 mmol) and was added     and the reaction was heated at 90° C. for 2.5 hours. The reaction     was cooled to ambient temperature, poured into ice-water (200 ml)     and the solid which precipitated was collected by suction filtration     to yield     (3-{[7-(benzyloxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetic acid     (3.92 g, 60% yield) as a pale orange solid:

¹H-NMR (DMSO d₆): 12.70 (br s, 1H), 8.75 (s, 1H), 8.70 (d, 1H), 7.57 (m, 2H), 7.35-7.50 (m, 4H), 7.30 (s, 1H), 6.70 (s, 1H), 5.35 (s, 2H), 3.70 (s, 2H):

MS (+ve ESI):376 (M+H)⁺,

MS (−ve ESI):374 (M−H)⁻.

-   b) Phosphorus oxychloride (1.00 ml, 11.6 mmol) was added to a     stirred suspension of 2,3-difluoroaniline (1.44 g, 11.6 mmol),     (3-{[7-(benzyloxy)quinazolin-4-yl]amino})-1H-pyrazol-5-yl)acetic     acid (3.82 g, 9.30 mmol) and pyridine (40 ml) at 0° C. The reaction     was stirred for 1 hour at ambient temperature, then cooled to 0° C.     and treated with additional phosphorus oxychloride (0.5 ml) before     being allowed to warm to ambient temperature over 1 hour. The     reaction was poured into 20% aqueous hydrochloric and the resultant     solid was collected by suction filtration. Prolonged drying in     vacuo, yielded     2-(3-{[7-(benzyloxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(2,3-difluorophenyl)acetamide     (4.90 g, 100% yield) as an orange solid which contained some water:

¹H-NMR (DMSO d₆): 11.30 (s, 1H), 10.30 (s, 1H), 8.80 (s, 1H), 8.70 (d, 1H), 7.80-7.80 (m, 1H), 7.50-7.60 (m, 2H), 7.35-7.45 (m, 5H), 7.30 (s, 1H), 7.10-7.20 (m, 2H), 6.80 (s, 1H), 5.40 (s, 2H), 3.90 (s, 2H):

MS (+ve ESI):487 (M+H)⁺,

MS (−ve ESI):485 (M−H)⁻.

-   c)     2-(3-{[7-(benzyloxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(2,3-difluorophenyl)acetamide     (4.90 g, 9.30 mmol) was added to trifluoroacetic acid (75 ml) and     the reaction heated at 90° C. for 4 hours. The reaction was cooled,     the excess trifluoroacetic acid was removed in vacuo and the residue     was taken up in methanol (30 ml). The methanolic solution was added     dropwise to aqueous sodium hydrogen carbonate solution (100 ml)     causing precipitation of an orange solid. Collection of the solid     followed by washing with water yielded     N-(2,3-difluorophenyl)-2-{3-[(7-hydroxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (3.60 g, 97% yield) as a pale brown solid after drying in vacuo:

¹H-NMR (DMSO d₆): 12.50 (br s, 1H), 10.30 (s, 1H), 8.70 (s, 1H), 8.60 (d, 1H), 7.70-7.80 (m, 1H), 7.30-7.40 (m, 2H), 7.10 (d, 1H), 7.00 (s, 1H), 6.80 (br s, 1H), 3.80 (s, 2H):

MS (+ve ESI):397 (M+H)⁺,

MS (−ve ESI):395 (M−H)⁻.

-   d) Methanesulphonyl chloride (864 mg, 7.58 mmol) was added dropwise     to a solution of N-(tert-butoxycarbonyl)piperidin-4-ylmethanol (1.63     g, 7.58 mmol) and triethylamine (1.40 ml, 10.0 mmol) in dry     tetrahydrofuran (15 ml) at 0° C. and the reaction was stirred at     this temperature for 1 hour. The reaction was filtered, the residue     was washed with diethyl ether and the combined organic phases were     evaporated in vacuo to afford a colourless oil. The oil was taken up     in dimethylacetamide (10 ml),     N-(2,3-difluorophenyl)-2-{3-[(7-hydroxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (2.00 g, 5.07 mmol) and potassium carbonate (1.39 g, 10.0 mmol) were     added and the reaction heated at 70° C. for 16 hours. The reaction     mixture was concentrated in vacuo and purified by flash     chromatography on silica gel, eluting with 0-5% methanol in     dichloromethane, to yield tert-butyl     4-[({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)methyl]piperidin-1-ylcarboxylate     (1.11 g, 38% yield) as a yellow solid:

¹H-NMR (DMSO d₆): 12.50 (s, 1H), 10.30 (d, 2H), 8.60-8.70 (m, 2H), 7.70-7.80 (m, 1H), 7.30-7.40 (m, 4H), 6.90 (s, 1H), 4.00-4.10 (m, 4H), 3.90 (s, 2H), 2.80-2.90 (m, 2H), 2.00-2.10 (m, 1H), 1.80-1.90 (m, 2H), 1.50 (s, 9H), 1.30-1.40 (m, 2H):

MS (+ve ESI):594 (M+H)⁺,

MS (−ve ESI):592 (M−H)⁻.

-   e) Trifluoroacetic acid (5 ml) was added to a solution of tert-butyl     4-[({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)methyl]piperidin-1-ylcarboxylate     (1.11 g, 1.897 mmol) in dichloromethane (25 ml) and the reaction     stirred for 30 minutes at ambient temperature. The volatile     substances were removed in vacuo and the product was purified by     reverse phase hplc. The fractions from the hplc were concentrated in     vacuo to 20% of their original volume and made basic with sodium     carbonate, causing precipitation of an orange solid. The solid was     collected by suction filtration, dissolved in     dichloromethane:methanol (1:9) and washed with water. Solvent     evaporation in vacuo yielded     N-(2,3-difluorophenyl)-2-(3-{[7-(piperidin-4-ylmethoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetamide     (612 mg, 66% yield) as an orange powdery solid:

¹H-NMR (DMSO d₆): 12.40 (s, 1H), 10.20 (br s, 2H), 8.50-8.60 (m, 2H), 7.70-7.80 (m, 1H), 7.00-7.20 (m, 4H), 6.70 (br s, 1H), 4.20 (br s, 1H), 4.00 (d, 2H), 3.90 (s, 2H), 3.10-3.20 (m, 2H), 2.90-3.00 (m, 2H), 1.90-2.00 (m, 1H), 1.70-1.80 (m, 2H), 1.20-1.30 (m, 2H):

MS (+ve ESI):494 (M+H)⁺,

MS (−ve ESI):492 (M−H)⁻.

-   f) Sodium acetoxyborohydride (392 mg, 1.86 mmol) was added to a     solution of tert-butyldimethylsilyloxyacetaldehyde (324 mg, 1.86     mmol),     N-(2,3-difluorophenyl)-2-(3-{[7-(piperidin-4-ylmethoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetamide     (612 mg, 1.24 mmol), acetic acid (0.42 ml, 7.4 mmol) in methanol     (10 ml) and tetrahydrofuran (30 ml) and the reaction stirred for 18     hours at ambient temperature. Additional sodium acetoxyborohydride     (392 mg, 1.86 mmol) and tert-butyldimethylsilyloxyacetaldehyde (324     mg, 1.86 mmol) were added and the reaction stirred for 10 minutes     before being concentrated in vacuo. The residue was purified by     flash chromatography on a Biotage 40M cartridge, eluting with     methanol:dichloromethane (7:93) and then 7.0N ammonia:methanol     (1:99) to give     2-{3-[(7-{[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)piperidin-4-yl]methoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide     (410 mg, 51% yield) as a pale orange solid after solvent evaporation     and drying in vacuo:

¹H-NMR (DMSO d₆): 12.40 (s, 1H), 10.15 (s, 1H), 10.10 (s, 1H), 8.50 (s, 1H), 8.45 (d, 1H), 7.60-7.70 (m, 1H), 7.00-7.20 (m, 4H), 6.70 (s, 1H), 3.90 (d, 2H), 3.70 (s, 2H), 3.60 (t, 2H), 2.80-2.90 (m, 2H), 2.40 (t, 2H), 1.90-2.00 (m, 2H), 1.70-1.80 (m, 3H), 1.20-1.30 (m, 2H), 0.80 (s, 9H), 0.00 (s, 6H):

MS (+ve ESI):652 (M+H)⁺,

MS (−ve ESI):650 (M−H)⁻.

-   g) Tetra-n-butylammonium fluoride (0.69 ml of a 1.0N solution in     tetrahydrofuran, 0.69 mmol) was added to a solution of     2-{3-[(7-{[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)piperidin-4-yl]methoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide     (410 mg, 0.63 mmol) in tetrahydrofuran (10 ml). The reaction was     stirred for 18 hours at ambient temperature, during which time 2     additional portions of tetra-n-butylammonium fluoride (0.69 mmol)     were added. The reaction was concentrated in vacuo and the residue     was purified by flash chromatography on a Biotage 40S cartridge,     eluting with methanol:dichloromethane (25:75) and then 7.0N ammonia     :methanol (1:99) to give     N-(2,3-difluorophenyl)-2-{3-[(7-{[1-(2-hydroxyethyl)piperidin-4-yl]methoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (258 mg, 76% yield) as a pale orange solid:

¹H-NMR (DMSO d₆): 12.30 (s, 1H), 10.30 (br s, 1H), 8.50 (br s, 2H), 7.76 (m, 1H), 7.10-7.40 (m, 4H), 6.90 (br s, 1H), 4.40 (br s, 1H), 4.10 (d, 2H), 3.80 (br s, 2H), 3.40-3.50 (m, 2H), 2.90-3.00 (m, 2H), 2.50 (t, 2H), 2.00-2.10 (m, 2H), 1.70-1.80 (m, 3H), 1.30-1.40 (m, 2H):

MS (+ve ESI):538 (M+H)⁺,

MS (−ve ESI):536 (M−H)⁻.

-   h) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{1-(2-hydroxyethyl)piperidin-4-yl]methoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (235 mg, 0.44 mmol) yielded di-tert-butyl     2-{4-[({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)methyl]piperidin-1-yl}ethyl     phosphate (232 mg, 73% yield) as a white solid:

¹H-NMR (DMSO d₆): 12.30 (s, 1H), 10.20 (d, 2H), 8.40 (br s, 2H), 7.60-7.70 (m, 1H), 7.30-7.40 (m, 4H), 6.80 (br s, 1H), 4.05 (d, 2H), 3.92 (m, 2H), 3.80 (br s, 2H), 2.80-2.90 (m, 2H), 2.50 (t, 2H), 2.00-2.10 (m, 2H), 1.60-1.70 (m, 3H), 1.40 (s, 18H), 1.20-1.30 (m, 2H):

MS (+ve ESI):730 (M+H)⁺,

MS (−ve ESI):728 (M−H)⁻.

EXAMPLE 28 Preparation of Compound 28 in Table 3—2-[[3-({4-[(5-[2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di(tert-butyl) 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl phosphate (302 mg, 0.422 mmol) yielded compound 28 in table 3 (300 mg, 100% yield) as a white solid:

¹H-NMR (DMSO d₆): 12.00 (s, 1H), 10.30 (s, 1H), 8.90 (d, 1H), 7.65-7.75 (m, 1H), 7.50-7.60 (m, 2H), 7.10-7.25 (m, 2H), 6.70 (s, 1H), 4.35 (t, 2H), 4.20-4.30 (m, 2H), 3.90 (s, 2H), 3.40-3.50 (m, 2H), 3.25-3.35 (m, 2H), 3.10-3.20 (m, 2H), 2.20-2.40 (M, 2H), 1.30 (t, 3H):

MS (+ve ESI):606 (M+H)⁺,

MS (−ve ESI):604 (M−H)⁻.

di(tert-butyl) 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a) 2-Amino-4-fluorobenzoic acid (15 g, 96 mmol) was dissolved in     2-methoxyethanol (97 ml). Formamidine acetate (20.13 g, 193.4 mmol)     was added and the mixture heated to reflux for 18 hours. The     reaction was cooled, concentrated and the residue stirred in aqueous     ammonium hydroxide (0.01 N, 250 ml) for 1 hour. The suspension was     filtered, washed with water and dried over phosphorus pentoxide to     yield 7-fluoroquinazolin-4(3H)-one as an off-white solid (10.35 g,     65% yield):

¹H-NMR (DMSO d₆): 12.32 (br s, 1H), 8.19 (dd, 1H), 8.14 (s, 1H), 7.45 (dd, 1H), 7.39 (m, 1H):

MS (−ve ESI):163 (M−H)⁻,

MS (+ve ESI):165 (M+H)⁺.

-   b) Sodium hydride (14.6 g, 365 mmol) was added at 0° C. to a     solution of 1,3-propanediol (27.8 g, 365 mmol) in dimethylformamide     (70 ml). 7-Fluoroquinazolin-4(3H)-one (10 g, 60.9 mmol) was added     portionwise and the reaction mixture heated at 60° C., then at     110° C. for 3 hours. The reaction was cooled to 0° C., quenched with     water (280 ml) and adjusted to pH 5.9. The resulting suspension was     filtered, washed with water then ether and dried over phosphorus     pentoxide to afford 7-(3-hydroxypropoxy)quinazolin-4(3H)-one as a     white powder (12.41 g, 92% yield):

¹H-NMR (DMSO d₆): 11.90 (br s, 1H), 8.04 (s, 1H), 8.00 (d, 1H), 7.10 (m, 2H), 4.17 (t, 2H), 3.58 (t, 2H), 1.92 (m, 2H):

MS (+ve ESI):221 (M+H)⁺.

-   c) 7-(3-hydroxypropoxy)quinazolin-4(3H)-one (10.5 g, 47.7 mmol) and     thionyl chloride (100 ml, 137 mmol) were combined. Dimethylformamide     (1 ml) was added and the reaction mixture heated to 85° C. for 1     hour. The mixture was cooled to room temperature, diluted with     toluene and evaporated to dryness. This was repeated until all     thionyl chloride was removed. The residue was dissolved in     dichloromethane and washed with a saturated sodium bicarbonate     solution. The aqueous layer was extracted with dichloromethane. The     organics were combined, dried (magnesium sulphate) and concentrated     to leave a yellow solid. Trituration with ether removed a less     soluble impurity and the ether filtrate was concentrated to leave     4-chloro-7-(3-chloropropoxy)quinazoline as an off-white solid (8.5     g, 70% yield):

¹H-NMR (DMSO d₆): 13.25 (br s, 1H), 8.34 (s, 1H), 8.06 (d, 1H), 7.17 (m, 2H), 4.21 (t, 2H), 3.83 (t, 2H), 2.23 (m, 2H):

MS (+ve ESI):257, 259 (M+H)⁺.

-   d) 4-chloro-7-(3-chloropropoxy)quinazoline (2.5 g, 9.72 mmol) and     (3-amino-1H-pyrazol-5-yl)acetic acid (1.37 g, 9.72 mmol) were     combined in dimethylformamide (25 ml). A solution of 4M HCl in     dioxane (1.25 ml, 4.8 mmol) was added and the reaction heated to     90° C. for 40 minutes. The solution was cooled to room temperature,     diluted with water (250 ml) and filtered through celite. The acidic     solution was basified to pH 4.9 and the yellow powder filtered. (At     pH 3, a red solid precipitated which was isolated, suspended in     water and basified to pH 12. Careful adjustment back to pH 4.8     resulted in the precipitation of a yellow powder, which was combined     with the first crop). The solid was washed with diethyl ether and     dried over phosphorus pentoxide to yield     (3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetic     acid as a pale orange solid (2.88 g, 82% yield):

¹H-NMR (DMSO d₆): 12.60 (br s, 2H), 10.78 (br s, 1H), 8.65 (s, 1H), 8.60 (d, 1H), 7.26 (d, 1H), 7.22 (s, 1H), 6.67 (s, 1H), 4.28 (t, 2H), 3.83 (t, 2H), 3.67 (s, 2H), 2.24 (m, 2H)

MS (−ve ESI):360, 362 (M−H)⁻,

MS (+ve ESI):362, 364 (M+H)⁺.

-   e) 2,3-difluoroaniline (1.15 g, 8.95 mmol) was added to a suspension     of     (3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetic     acid (2.70 g, 7.46 mmol) in pyridine (30 ml) and the reaction cooled     to 0° C. Phosphorous oxychloride (1.14 g, 7.46 mmol) was added     dropwise and the reaction stirred at 0° C. for 1 hour. The reaction     was warmed to ambient temperature and more phosphorous oxychloride     (0.5 ml) added. The reaction was stirred for 4.5 hours. The reaction     mixture was diluted with ethyl acetate: ether (100 ml:37 ml) and     stirred for 18 hours. The precipitate was filtered, suspended in     water and neutralised with ammonium hydroxide (7%, 15 ml). The     resultant yellow suspension was filtered, washed with water and     dried (phosphorous pentoxide) to yield     2-(3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino)-1H-pyrazol-5-yl)-N-(2,3-difluorophenyl)acetamide     as an orange powder (3.15 g, 89% yield):

¹H-NMR (DMSO d₆): 10.64 (br s, 1H), 10.27 (s, 1H), 8.60 (s, 1H), 8.55 (d, 1H), 7.70 (m, 1H), 7.20 (m, 6H), 6.68 (s, 1H), 4.27 (t, 2H), 3.83 (m, 4H), 2.25 (m, 2H):

MS (−ve ESI):471, 473 (M−H)⁻,

MS (+ve ESI):473, 475 (M+H)⁺.

-   f)     2-(3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(2,3-difluorophenyl)acetamide     (300 mg, 0.634 mmol), potassium iodide (210 mg, 1.27 mmol),     dimethylamine (2 ml) and 2-(ethylamino)ethanol (226 mg, 2.54 mmol)     were combined and heated to 50° C. for 72 hours. The reaction was     diluted with dichloromethane (20 ml) and loaded onto a 40S silica     biotage column. Elution with dichloromethane followed by increased     polarity to dichloromethane:methanol (9:1), then dichloromethane:     methanol: ammonia (9:1:0.8) yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as a pale pink solid (181 mg, 54% yield):

¹H-NMR (DMSO d₆): 12.35 (s, 1H), 10.25 (s, 2H), 8.52 (s, 2H), 7.71 (m, 1H), 7.16 (m, 4H), 6.78 (s, 1H), 4.33 (t, 1H), 4.17 (t, 2H), 3.84 (s, 2H), 3.43 (m, 2H), 2.60 (t, 2H), 2.49 (m, 4H), 1.88 (m, 2H), 0.96 (t, 3H):

MS (−ve ESI):524 (M−H)⁻,

MS (+ve ESI):526 (M+H)⁺.

-   g) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (372 mg, 0.71 mmol) yielded di(tert-butyl)     2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl     phosphate (304 mg, 60% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 12.30 (s, 1H), 10.20 (d, 2H), 8.60-8.70 (m, 2H), 7.70-7.80 (m, 1H), 7.05-7.25 (m, 4H), 6.80 (br s, 1H), 4.20 (t, 2H), 3.80-3.90 (m, 4H), 2.60-2.70 (m, 4H), 2.40-2.50 (m, 2H), 1.80-1.90 (m, 2H), 1.40 (s, 18H), 0.95 (t, 3H):

MS (+ve ESI):718 (M+H)⁺,

MS (−ve ESI):716 (M−H)⁻.

EXAMPLE 29 Preparation of Compound 29 in Table 3—2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl)-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](isopropyl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](isopropyl)amino]ethyl phosphate (372 mg, 0.51 mmol) yielded compound 29 in table 3 (342 mg, 92% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 12.00 (s, 1H), 10.30 (s, 1H), 8.90 (s, 1H), 8.80 (d, 1H), 7.60-7.70 (m, 1H), 7.40-7.50 (m, 2H), 7.10-7.20 (m, 2H), 6.70 (s, 1H), 4.40 (t, 2H), 4.20-4.30 (m, 2H), 3.90 (s, 2H), 3.70-3.80 (m, 1H), 3.40-3.50 (m, 2H), 3.20-3.30 (m, 2H), 2.30-2.40 (m, 2H), 1.35 (d, 6H):

MS (+ve ESI):620 (M+H)⁺,

MS (−ve ESI):618 (M−H)⁻.

di-tert-butyl 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](isopropyl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 28f, but     starting with 2-(isopropylamino)ethanol (262 mg, 2.54 mmol) yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[isopropyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as an off-white solid (182 mg, 53% yield):

¹H-NMR (DMSO d₆): 12.35 (s, 1H), 10.20 (s, 1H), 8.50 (s, 2H), 7.71 (m, 1H), 7.20 (m, 4H), 6.78 (s, 1H), 4.29 (br s, 1H), 4.19 (t, 2H), 3.85 (s, 2H), 3.38 (dt, 2H), 2.88 (m, 1H), 2.55 (t, 2H), 2.45 (t, 2H), 1.82 (m, 2H), 0.93 (d, 6H):

MS (−ve ESI):538 (M−H)⁻,

MS (+ve ESI):540 (M+H)⁺.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[isopropyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (414 mg, 0.77 mmol) yielded di-tert-butyl     2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](isopropyl)amino]ethyl     phosphate (374 mg, 67% yield) as a white solid:

¹H-NMR (DMSO d₆): 12.40 (s, 1H), 10.20 (d, 2H), 8.50-8.60 (m, 2H), 7.60-7.80 (m, 1H), 7.10-7.30 (m, 4H), 6.80 (br s, 1H), 4.15-4.25 (m, 2H), 3.80-3.90 (m, 4H), 2.85-3.00 (m, 1H), 2.50-2.65 (m, 4H), 1.80-1.90 (m, 2H), 1.40 (s, 18H), 1.00 (s, 3H), 0.98 (s, 3H):

MS (+ve ESI):b 732 (M+H)⁺,

MS (−ve ESI):730 (M−H)⁻.

EXAMPLE 30 Preparation of Compound 30 in Table 3—3-{[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}-3-methylbutyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 3-{[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}-3-methylbutyl phosphate (490 mg, 0.67 mmol) yielded compound in table 3 (480 mg, 99% yield) as a pale yellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 12.00 (s, 1H), 10.35 (s, 1H), 9.20 (br s, 1H), 8.90 (s, 1H), 8.80 (d, 1H), 7.72 (m, 1H), 7.50 (d, 2H), 7.40 (s, 1H), 7.20-7.30 (m, 2H), 6.70 (s, 1H), 4.30 (t, 2H), 3.90-4.00 (m, 2H), 3.85 (s, 2H), 3.10-3.20 (m, 2H), 2.20-2.30 (m, 2H), 2.00-2.10 (m, 2H), 1.40 (d, 6H):

MS (+ve ESI):620 (M+H)⁺.

MS (−ve ESI):618 (M−H)⁻.

di-tert-butyl 3-{[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}-3-methylbutyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 28f, but     starting with 3-amino-3-methylbutan-1-ol (655 mg, 6.36 mmol) yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(3-hydroxy-1,1-dimethylpropyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as an off-white solid (450 mg, 39% yield):

¹H-NMR (DMSO d₆): 12.40 (s, 1H), 10.20 (br s, 2H), 8.60-8.70 (m, 2H), 7.70-7.80 (m, 1H), 7.25-7.35 (m, 4H), 6.80 (br s, 1H), 4.20 (t, 2H), 3.90 (s, 2H), 3.60 (t, 2H), 2.70 (t, 2H), 1.90-2.00 (m, 2H), 1.50 (t, 2H), 1.00 (s, 6H):

MS (+ve ESI):540 (M+H)⁺,

MS (−ve ESI):538 (M−H)⁻.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(3-hydroxy-1,1-dimethylpropyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (212 mg, 0.38 mmol) yielded di-tert-butyl     3-{[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}-3-methylbutyl     phosphate (204 mg, 72% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 12.40 (s, 1H), 10.20 (d, 2H), 8.50-8.60 (m, 2H), 7.65-7.75 (m, 1H), 7.20-7.30 (m, 4H), 6.80 (s, 1H), 4.30 (t, 2H), 3.90-4.00 (m, 2H), 3.85 (s, 2H), 2.70-2.80 (m, 2H), 1.90-2.00 (m, 2H), 1.60-1.70 (m, 2H), 1.40 (s, 18H), 1.10 (s, 6H):

MS (+ve ESI):732 (M+H)⁺,

MS (−ve ESI):730 (M−H)⁻.

EXAMPLE 31 Preparation of Compound 31 in Table 3—2-{(2S)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di(tert-butyl) 2-{(2S)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}ethyl phosphate (204 mg, 0.27 mmol) yielded compound 31 in table 3 (198 mg, 97% yield) as a pale yellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 12.00 (s, 1H), 10.80 (s, 1H), 10.50 (s, 1H), 8.95 (s, 1H), 8.80 (d, 1H), 7.60-7.80 (m, 1H), 7.50 (d, 1H), 7.40 (s, 1H), 7.20-7.30 (m, 2H), 6.70 (s, 1H), 4.35 (t, 2H), 3.90-4.00 (m, 1H), 3.85 (s, 2H), 3.60-3.70 (m, 1H), 3.30-3.50 (m, 2H), 3.00-3.25 (m, 2H), 2.20-2.40 (m, 4H), 1.90-2.10 (m, 3H), 1.70-1.80 (m, 1H):

MS (+ve ESI):632 (M+H)⁺,

MS (−ve ESI):630 (M−H)⁻.

di(tert-butyl) 2-{(2S)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 28f, but     starting with (2S)-2-(2-hydroxyethyl)pyrrolidine (731 mg, 6.36 mmol)     yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(2-hydroxyethyl)pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as a white solid (260 mg, 22% yield):

¹H-NMR (DMSO d₆): 12.30 (s, 1H), 10.20 (s, 2H), 8.40-8.70 (m, 2H), 7.70-7.80 (m, 1H), 7.10-7.30 (m, 4H), 6.80 (br s, 1H), 4.30-4.50 (m, 1H), 4.20 (t, 2H), 3.80-3.90 (m, 2H), 3.30-3.50 (m, 2H), 3.10-3.20 (m, 1H), 2.90-3.00 (m. 1H), 2.30-2.40 (m, 1H), 2.10-2.20 (m, 1H), 1.90-2.00 (m, 1H), 1.75-1.85 (m, 3H), 1.68 (m, 1H), 1.50-1.60 (m, 2H), 1.30-1.40 (m, 2H):

MS (+ve ESI):520 (M+H)⁺,

MS (−ve ESI):550 (M−H)⁻.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(2-hydroxyethyl)pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (212 mg, 0.38 mmol) yielded di(tert-butyl)     2-{(2S)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}ethyl     phosphate (204 mg, 72% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆, 373K): 12.00 (s, 1H), 9.90 (s, 2H), 9.80 (s, 1H), 8.50 (s, 1H), 8.40 (d, 1H), 7.70-7.80 (m, 1H), 7.20-7.30 (m, 4H), 6.70 (br s, 1H), 4.30 (t, 2H), 3.90-4.00 (m, 2H), 3.80 (s, 2H), 3.00-3.10 (m, 1H), 2.40-2.50 (m, 1H), 2.20-2.30 (m, 1H), 1.80-2.00 (m, 4H), 1.70-1.80 (m, 2H), 1.62 (m, 1H), 1.40-1.50 (m, 1H), 1.40 (s, 18H), 0.90-1.00 (m, 1H):

MS (+ve ESI):742 (M+H)⁺,

MS (−ve ESI): 740 (M−H)⁻.

EXAMPLE 32 Preparation of Compound 32 in Table 3—{(2R)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}1-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di(tert-butyl) {(2R)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl phosphate (355 mg, 0.49 mmol) yielded compound 32 in table 3 (355 mg, 100% yield) as a pale yellow dihydrochloride salt (as the dihydrate):

¹H-NMR (DMSO d₆): 12.00 (br s, 1H), 10.40 (s, 1H), 8.93 (s, 1H), 8.82 (d, 1H), 7.68 (m, 1H), 7.40-7.50 (m, 2H), 7.15-7.25 (m, 2H), 6.75 (s, 1H), 4.35 (t, 2H), 4.10-4.30 (m, 1H), 3.92 (s, 2H), 3.81 (m, 1H), 3.55-3.70 (m, 2H), 3.27 (m, 1H), 3.18 (m, 1H), 2.10-2.35 (m, 4H), 1.85-2.10 (m, 3H), 1.75-1.85 (m, 1H):

MS (+ve ESI):618 (M+H)⁺.

di(tert-butyl) {(2R)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 28f, but     starting with D-prolinol (257 mg, 2.54 mmol) yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as a pink solid (206 mg, 60% yield):

¹H-NMR (DMSO d₆): 11.60 (br s, 7H), 10.25 (s, 1H), 8.52 (m, 2H), 7.75 (m, 1H), 7.16 (m, 4H), 6.67 (s, 1H), 4.22 (t, 2H), 3.84 (s, 2H), 3.50 (d, 2H), 3.35 (m, 1H), 3.28 (m, 1H), 3.07 (m, 1H), 2.86 (m, 1H), 2.72 (m, 1H), 2.05 (m, 2H), 1.95 (m, 1H), 1.60-1.90 (m, 4H):

MS (−ve ESI):536 (M−H)⁻,

MS (+ve ESI):538 (M+H)⁺.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (437 mg, 0.81 mmol) yielded di(tert-butyl)     {(2R)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     phosphate (355 mg, 60% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 12.30 (br s, 1H), 10.20 (s, 2H), 8.50 (s, 2H), 7.68 (m, 1H), 7.10-7.20 (m, 4H), 6.78 (br s, 1H), 4.15 (t, 2H), 3.80 (m, 3H), 3.65 (m, 1H), 3.10 (m, 1H), 2.93 (m, 1H), 2.64 (m, 1H), 2.19 (m, 1H), 1.80-1.95 (m, 3H), 1.68 (m, 2-H), 1.60 (m, 1H), 1.33 (s, 18H):

MS (−ve ESI):728 (M−H)⁻,

MS (+ve ESI):730 (M+H)⁺.

EXAMPLE 33 Preparation of Compound 33 in Table 3—2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl)-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl phosphate (271 mg, 0.37 mmol) yielded compound 33 in table 3 (266 mg, 98% yield) as the dihydrochloride salt:

¹H-NMR (DMSO d₆): 12.02 (br s, 1H), 10.40 (s, 1H), 9.95 (s, 1H), 9.85 (s, 1H), 7.70 (s, 1H), 7.47 (m, 2H), 7.20 (m, 2H), 6.73 (s, 1H), 4.23-4.37 (m, 4H), 3.92 (s, 2H), 3.43 (m, 2H), 3.32 (m, 2H), 3.13 (n, 2H), 2.28 (m, 2H), 1.76 (m, 2H), 0.95 (t, 3H):

MS (+ve ESI):618.4 (M+H)⁺,

MS (−ve ESI):620.4 (M−H)⁻.

di-tert-butyl 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 28f, but     starting with 2-(propylamino)ethanol (262 mg, 2.54 mmol) yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as a pink solid (168 mg, 49% yield):

¹H-NMR (DMSO d₆): 12.35 (s, 1H), 10.22 (s, 2H), 8.51 (s, 2H), 7.71 (m, 1H), 7.20 (m, 4H), 6.78 (s, 1H), 4.30 (t, 1H), 4.17 (t, 2H), 3.85 (s, 2H), 3.43 (m, 2H), 2.59 (t, 2H), 2.49 (m, 2H), 2.39 (t, 2H), 1.87 (m, 2H), 1.39 (m, 2H), 0.82 (t, 3H):

MS (−ve ESI):538 (M−H)⁻,

MS (+ve ESI):540 (M+H)⁺.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (690 mg, 1.28 mmol) yielded di-tert-butyl     2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     phosphate (271 mg, 29% yield) as a pale yellow solid:

MS (−ve ESI):730 (M−H)⁻,

MS (+ve ESI):732 (M+H)⁺.

EXAMPLE 34 Preparation of Compound 34 in Table 3—2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](butyl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di(tert-butyl) 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](butyl)amino]ethyl phosphate (400 mg, 0.54 mmol) yielded compound 34 in table 3 (360 mg, 95% yield) as a pale yellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 12.00 (s, 1H), 10.34 (s, 1H), 8.93 (s, 1H), 8.85 (d, 1H), 7.68 (m, 1H), 7.47 (d, 1H), 7.44 (s, 1H), 7.20 (m, 2H), 6.74 (s, 1H), 4.33 (t, 2H), 4.28 (m, 2H), 3.93 (s, 2H), 3.44 (m, 2H), 3.36 (m, 2H), 3.16 (m, 2H), 2.30 (m, 2H), 1.71 (m, 2H), 1.34 (m, 2H), 0.93 (t, 3H):

MS (+ve ESI):634 (M+H)⁺.

di(tert-butyl) 2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](butyl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 28f, but     starting with 2-(butylamino)ethanol (891 mg, 7.61 mmol) yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(butyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as a pale yellow solid (625 mg, 45% yield):

¹H-NMR (DMSO d₆): 12.65 (s, 1H), 12.32 (s, 1H), 10.17 (m, 2H), 8.52 (m, 2H), 7.72 (m, 1H), 7.05-7.30 (m, 4H), 6.78 (br s, 1H), 4.30 (m, 1H), 4.20 (t, 2H), 3.85 (br s, 2H), 3.44 (m, 2H), 2.63 (m, 2H), 2.54 (m, 2H), 2.45 (m, 2H), 1.90 (m, 2H), 1.38 (m, 2H), 1.26 (m, 2H), 0.84 (t, 3H):

MS (+ve ESI):554 (M+H)⁺.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(butyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (605 mg, 1.09 mmol) yielded di(tert-butyl)     2-[[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](butyl)amino]ethyl     phosphate (400 mg, 50% yield) as a pale yellow solid:

¹H-NMR (CDCl₃): 12.80 (br s, 1H), 9.47 (br s, 1H), 9.40 (br s, 1H), 8.72 (s, 1H), 8.13 (d, 1H), 8.05 (m, 1H), 7.22 (s, 1H), 7.18 (d, 1H), 7.03 (m, 1H), 6.86 (m, 1H), 6.15 (br s, 1H), 4.15 (t, 2H), 4.00 (q, 2H), 3.83 (s, 2H), 2.73 (t, 2H), 2.64 (t, 2H), 2.47 (t, 2H), 1.93 (m, 2H), 1.48 (s, 18H), 1.44 (m, 2H), 1.29 (m, 2H), 0.89 (t, 3H):

MS (+ve ESI):746 (M+H)⁺.

EXAMPLE 35 Preparation of Compound 35 in Table 3—2-{cyclopentyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]amino}ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-{cyclopentyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]amino}ethyl phosphate (405 mg, 0.53 mmol) yielded compound 35 in table 3 (388 mg, 100% yield) as a pale yellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 12.00 (s, 1H), 10.33 (s, 1H), 8.93 (s, 1H), 8.83 (d, 1H), 7.69 (m, 1H), 7.49 (d, 1H), 7.41 (s, 1H), 7.20 (m, 2H), 6.74 (s, 1H), 4.32 (t, 2H), 4.29 (m, 2H), 3.93 (s, 2H), 3.77 (m, 1H), 3.46 (m, 2H), 3.35 (m, 2H), 2.31 (m, 2H), 2.08 (m, 2H), 1.83 (m, 2H), 1.74 (m, 2H), 1.57 (m, 2H):

MS (+ve ESI):646 (M+H)⁺.

di-tert-butyl 2-{cyclopentyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]amino}ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 28f, but     starting with 2-(cyclopentylamino)ethanol (1.00 g, 7.75 mmol)     yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as a pale yellow solid (533 mg, 37% yield):

¹H-NMR (DMSO d₆): 12.66 (s, 1H), 12.30 (s, 1H), 10.16 (m, 2H), 8.52 (m, 2H), 7.72 (m, 1H), 7.06-7.40 (m, 4H), 6.80 (s, 1H), 4.32 (n 1H), 4.19 (t, 2H), 3.85 (br s, 2H), 3.43 (m, 2H), 3.06 (m, 1H), 2.66 (m, 2H), 2.56 (m, 2H), 1.90 (m, 2H), 1.73 (m, 2H), 1.58 (m, 2H), 1.48 (m, 2H), 1.32 (m, 2H):

MS (+ve ESI):566 (M+H)⁺.

-   b) An analogous reaction to that described in example 6c, but     starting with     2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(2,3-difluorophenyl)acetamide     (482 mg, 0.85 mmol) yielded di-tert-butyl     2-{cyclopentyl[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]amino}ethyl     phosphate (411 mg, 64% yield) as a pale yellow solid:

¹H-NMR (CDCl₃): 12.70 (br s), 1H), 9.35 (m, 2H), 8.71 (s, 1H), 8.05 (m, 2H), 7.20 (s, 1H), 7.12 (d, 1H), 7.01 (m, 1H), 6.86 (m, 1H), 6.17 (br s), 1H), 4.11 (t, 2H), 3.98 (q, 2H), 3.83 (s, 2H), 3.08 (m, 1H), 2.80 (t, 2H), 2.72 (t, 2H), 1.95 (m, 2H), 1.78 (m, 2H), 1.69 (m, 2H), 1.62 (m, 2H), 1.50 (s, 18H), 1.35 (m, 2H):

MS (+ve ESI):758 (M+H)⁺.

EXAMPLE 36 Preparation of Compound 36 in Table 3—{(2S)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl)-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di(tert-butyl) {(2S)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl phosphate (425 mg, 0.58 mmol) yielded compound 36 in table 3 (400 mg, 99% yield) as an off-white solid:

¹H-NMR (DMSO d₆): 12.00 (s, 1H), 10.35 (s, 1H), 8.94 (s, 1H), 8.85 (d, 1H), 7.67 (m, 1H), 7.47 (d, 1H), 7.43 (s, 1H), 7.20 (m, 2H), 6.74 (s, 1H), 4.34 (t, 2H), 4.15-4.32 (m, 2H), 3.92 (s, 2H), 3.78 (m, 1H), 3.52-3.72 (m, 2H), 3.30 (m, 1H), 3.19 (m, 1H), 2.24-2.42 (m, 2H), 2.20 (m, 1H), 2.02 (m, 1H), 1.96 (m, 1H), 1.82 (m, 1H):

MS (+ve ESI):618 (M+H)⁺.

di(tert-butyl) {(2S)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 28f, but     starting with L-prolinol (770 mg, 7.62 mmol) yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as a pale yellow solid (547 mg, 40% yield):

¹H-NMR (DMSO d₆): 12.66 (s, 1H), 12.35 (s, 1H), 10.20 (m, 2H), 8.51 (m, 2H), 7.72 (m, 1H), 7.20 (m, 4H), 6.77 (br s, 1H), 4.21 (t, 2H), 3.81 (br s, 2H), 3.47 (m, 1H), 2.90-3.42 (m, 6H), 2.05 (m, 2H), 1.90 (m, 1H), 1.72 (m, 2H), 1.62 (m, 1H):

MS (+ve ESI):538 (M+H)⁺.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (485 mg, 0.90 mmol) yielded di(tert-butyl)     {(2S)-1-[3-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     phosphate (430 mg, 65% yield) as a pale yellow solid:

¹H-NMR (CDCl₃): 12.70 (br s, 1H), 9.52 (br s, 1H), 9.37 (br s, 1H), 8.10 (s, 1H), 8.06 (m, 1H), 7.18 (s, 1H), 7.11 (d, 1H), 7.02 (m, 1H), 6.85 (m, 1H), 6.22 (br s, 1H), 4.12 (m, 2H), 3.92 (m, 1H), 3.84 (s, 2H), 3.68 (m, 1H), 3.12 (m, 1H), 2.97 (m, 1H), 2.73 (m, 1H), 2.48 (m, 1H), 2.25 (q, 1H), 1.85-2.05 (m, 3H), 1.55-1.85 (m, 3H), 1.45 (s, 18H):

MS (+ve ESI): 730 (M+H)⁺.

EXAMPLE 37 Preparation of Compound 37 in table 3—{(2S)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di(tert-butyl) {(2S)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl phosphate (654 mg, 0.92 mmol) yielded compound 37 in table 3 (596 mg, 97% yield) as an off-white dihydrochloride salt:

¹H-NMR (DMSO d₆): 11.95 (s, 1H), 10.73 (s, 1H), 8.94 (s, 1H), 8.82 (d, 1H), 7.65 (d, 1H), 7.46 (d, 1H), 7.38 (m, 3H), 6.90 (m, 1H), 6.74 (s, 1H), 4.32 (t, 2H), 4.21 (m, 2H), 3.85 (s, 2H), 3.78 (m, 1H), 3.64 (m, 2H), 3.29 (m, 1H), 3.19 (q, 1H), 2.31 (m, 3H), 2.20 (m, 1H), 2.00 (m, 3H), 1.81 (m, 1H):

MS (+ve ESI): 599.8 (M+H)⁺.

di(tert-butyl) {(2S)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 28f, but     starting with L-prolinol (0.89 ml, 8.80 mmol) and     2-(3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide     (1.00 g, 2.20 mmol) yielded     N-(3-fluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as a cream solid (795 mg, 70% yield):

¹H-NM (DMSO d₆): 12.35 (m, 1H), 10.42 (s, 1H), 10.19 (m, 1H), 8.50 (s, 2H), 7.63 (d, 1H), 7.35 (m, 2H), 7.16 (m, 2H), 6.90 (t, 1H), 6.73 (m, 1H), 4.28 (t, 1H), 4.18 (t, 2H), 3.73 (s, 2H), 3.40 (m, 1H), 3.20 (m, 1H), 3.07 (m, 1H), 2.97 (m, 1H), 2.43 (m, 2H), 2.15 (q, 1H), 1.94 (m, 2H), 1.81 (m, 1H), 1.64 (m, 2H), 1.55 (m, 1H):

MS (+ve ESI): 520.1 (M+H)⁺.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(3-fluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (730 mg, 1.41 mmol) yielded di(tert-butyl)     {(2S)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     phosphate (654 mg, 65% yield) as a pale yellow solid which was used     in the next step without further characterisation.     2-(3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide     used as starting material was obtained as follows: -   c) Pentafluorophenyl trifluoroacetate (23.25 g, 83 mmol) was added     dropwise to a solution of     (3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetic     acid (15.0 g, 41 mmol) and pyridine (6.7 ml, 83 mmol) in     dimethylformamide (150 ml) with cooling to maintain the solution     temperature at <23° C. The solution was stirred at ambient     temperature for 30 minutes before addition of 3-fluoroaniline (9.22     g, 83 mmol). The reaction was stirred for 2.5 hours at ambient     temperature and then a further portion of 3-fluoroaniline (2 ml) was     added and the mixture was heated at 90° C. for 3 hours. The reaction     mixture was poured into dilute hydrochloric acid (0.1 M) and ice     (ca. 500 ml) and the resultant solid was filtered, washed with water     and then diethyl ether and then dried to give     2-(3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide     (17.7 g, 94% yield) as a brown solid:

¹H-NMR (DMSO d₆): 12.50 (br s, 1H), 10.42 (s, 1H), 8.59 (s, 1H), 8.54 (d, 1H), 7.62 (m, 1H), 7.35 (m, 2H), 7.24 (m, 1H), 7.19 (m, 1H), 6.90 (m, 1H), 6.67 (br s, 1H), 4.28 (t, 2H), 3.84 (t, 2H), 3.76 (s, 2H), 2.27 (quintet, 2H).

MS (+ve ESI): 455 (M+H)⁺.

EXAMPLE 38 Preparation of Compound 38 in Table 3—2-{cyclopentyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]amino}ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-{cyclopentyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]amino}ethyl phosphate (572 mg, 0.77 mmol) yielded compound 38 in table 3 (568 mg, 100% yield):

¹H-NMR (DMSO d₆): 11.95 (s, 1H), 10.73 (s, 1H), 8.94 (s, 1H), 8.82 (d, 1H), 7.65 (d, 1H), 7.48 (d, 1H), 7.38 (m, 3H), 6.89 (m, 1H), 6.75 (s, 1H), 4.30 (m, 4H), 3.85 (s, 2H), 3.78 (t, 1H), 3.47 (m, 2H), 3.37 (m, 2H), 2.60 (m, 2H), 2.08 (m, 2H), 1.78 (m, 4H), 1.56 (m, 2H):

MS (+ve ESI): 628.4 (M+H)⁺.

di-tert-butyl 2-{cyclopentyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]amino}ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 37a, but     starting with 2-(cyclopentylamino)ethanol (1.13 ml, 8.80 mmol)     yielded     2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide     as a cream solid (620 mg, 51% yield):

¹H-NMR (DMSO d₆): 12.31 (m, 1H), 10.39 (s, 1H), 10.16 (m, 1H), 8.50 (s, 2H), 7.62 (d, 1H), 7.35 (m, 2H), 7.16 (m, 2H), 6.90 (t, 1H), 6.78 (m, 1H), 4.29 (m, 1H), 4.16 (t, 2H), 3.74 (s, 2H), 3.40 (m, 2H), 3.05 (t, 1H), 2.66 (t, 2H), 2.54 (obs m, 2H), 1.86 (t, 2H), 1.72 (m, 2H), 1.54 (m, 2H), 1.45 (m, 2H), 1.31 (m, 2H)

MS (+ve ESI): 548.1 (M+H)⁺.

-   b) An analogous reaction to that described in example 6c, but     starting with     2-{3-[(7-{3-[cyclopentyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide     (580 mg, 1.06 mmol) yielded di-tert-butyl     2-{cyclopentyl[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]amino}ethyl     phosphate (572 mg, 72% yield) as a pale yellow solid which was used     in the next step without further characterisation.

EXAMPLE 39 Preparation of Compound 39 in Table 3—2-[[3-{4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di(tert-butyl) 2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl phosphate (539 mg, 0.77 mmol) yielded compound 39 in table 3 (504 mg, 99% yield) as a pale yellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 11.98 (s, 1H), 10.79 (s, 1H), 8.93 (s, 1H), 8.83 (d, 1H), 7.65 (d, 1H), 7.47 (d, 1H), 7.38 (m, 3H), 6.89 (t, 1H), 6.74 (s, 1H), 4.32 (t, 2H), 4.28 (m, 2H), 3.85 (s, 2H), 3.42 (m, 2H), 3.34 (m, 2H), 3.27 (q, 2H), 2.29 (m, 2H), 1.28 (t, 3H):

MS (+ve ESI): 587.8 (M+H)⁺.

di(tert-butyl) 2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 37a, but     starting with N-(ethylamino)ethanol (1.07 ml, 11.0 mmol) yielded     N-(3-fluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as a yellow solid (660 mg, 59% yield):

¹H-NMR (DMSO d₆): 12.31 (m, 1H), 10.39 (s, 1H), 10.15 (m, 1H), 8.51 (s, 2H), 7.62 (d, 1H), 7.35 (m, 2H), 7.16 (m, 2H), 6.90 (t, 1H), 6.78 (m, 1H), 4.29 (m, 1H), 4.20 (t, 2H), 3.76 (s, 2H), 3.45 (m, 2H), 3.30 (m, 4H), 2.61 (t, 2H), 1.89 (t, 2H), 0.95 (t, 3H):

MS (+ve ESI): 508.4 (M+H)⁺.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(3-fluorophenyl)-2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (620 mg, 1.22 mmol) yielded di(tert-butyl)     2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl     phosphate (539 mg, 63% yield) as a pale yellow solid which was used     in the next step without further characterisation.

Compound 39, synthesised above as the dihydrochloride salt, could also be prepared as the free base according to the following method: I

-   c) An analogous reaction to that described in example 6d, but     starting with Compound 39 yielded the free base of Compound 39 as a     pale yellow solid:

¹H-NMR (DMSO d₆): 10.53 (s, 1H), 8.57 (s, 1H), 8.54 (d, 1H), 7.62 (d, 1H), 7.37 (m, 2H), 7.27 (s, 1H), 7.21 (d, 1H), 6.88 (m, 1H), 6.65 (s, 1H), 4.27 (t, 2H), 4.05 (m, 2H), 3.75 (s, 2H), 3.24 (m, 2H), 3.21 (t, 2H), 3.13 (q, 2H), 2.18 (m, 2H), 1.24 (t, 3H):

MS (+ve ESI): 588 (M+H)⁺.

C₂₆H₃₁FN₇O₆P+3.0H₂O requires C, 48.7%; H, 5.8%; N, 15.3%; Found C, 48.8%; H, 5.35%; N, 15.15%.

EXAMPLE 40 Preparation of Compound 40 in Table 3—3-{[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl)-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}-3-methylbutyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 3-{[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}-3-methylbutyl phosphate (247 mg, 0.35 mmol) yielded compound 40 in table 3 (235 mg, 100% yield) as a pale yellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 11.98 (s, 1H), 10.76 (s, 1H), 8.94 (s, 1H), 8.83 (d, 1H), 7.65 (d, 1H), 7.48 (d, 1H), 7.37 (m, 3H), 6.89 (t, 1H), 6.75 (s, 1H), 4.35 (t, 2H), 4.00 (q, 2H), 3.85 (s, 2H), 3.11 (m, 2H), 2.26 (m, 2H), 2.05 (t, 2H), 1.35 (s, 6H):

MS (+ve ESI): 601.8 (M+H)⁺.

di-tert-butyl 3-{[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}-3-methylbutyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 37a, but     starting with 3-amino-3-methylbutan-1-ol (1.15 ml, 11.0 mmol)     yielded N-(3-fluorophenyl)-2-{3-[(7-{3-[(3-hydroxy-1,     1-dimethylpropyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as a pale yellow solid (310 mg, 27% yield):

¹H-NMR (DMSO d₆): 12.31 (m, 1H), 10.40 (m, 1H), 8.50 (m, 2H), 7.62 (d, 1H), 7.35 (m, 2H), 7.11 (m, 2H), 6.89 (t, 1H), 6.56 (m, 1H), 4.18 (t, 2H), 3.71 (s, 2H), 3.52 (t, 2H), 2.65 (t, 2H), 1.86 (m, 2H), 1.52 (t, 2H), 1.04 (s, 6H):

MS (+ve ESI): 522.5 (M+H)⁺.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(3-fluorophenyl)-2-{3-[(7-{3-[(3-hydroxy-1,1-dimethylpropyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (310 mg, 0.59 mmol) yielded di-tert-butyl     3-{[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}-3-methylbutyl     phosphate (247 mg, 58% yield) as a pale yellow solid which was used     in the next step without further characterisation.

EXAMPLE 41 Preparation of Compound 41 in Table 3—2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl)-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl phosphate (270 mg, 0.38 mmol) yielded compound 41 in table 3 (248 mg, 96% yield) as a dihydrochloride salt:

¹H-NMR (DMSO d₆): 11.98 (s, 1H), 10.77 (s, 1H), 8.96 (s, 1H), 8.84 (d, 1H), 7.65 (d, 1H), 7.46 (d, 1H), 7.32-7.41 (m, 3H), 6.88 (m, 1H), 6.73 (s, 1H), 6.73 (s, 1H), 4.32 (t, 2H), 4.27 (t, 2H), 3.87 (s, 2H), 3.43 (t, 2H), 3.14 (m, 2H), 2.28 (m, 2H), 1.75 (m, 2H), 0.94 (t, 3H):

MS (+ve ESI): 602 (M+H)⁺,

MS (−ve ESI): 600 (M−H)⁻.

di-tert-butyl 2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 37a, but     starting with 2-(propylamino)ethanol (0.89 g, 8.6 mmol) yielded     N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as a pale yellow solid (480 mg, 32% yield):

¹H-NMR (DMSO-d₆): 12.30 (br s, 1H), 10.38 (s, 1H), 10.15 (br s, 1H), 8.50 (s, 2H), 7.60 (d, 1H), 7.34 (m, 2H), 7.15 (br s, 2H), 6.90 (dd, 1H), 6.78 (br s, 1H), 4.30 (br s, 1H), 4.18 (t, 2H), 3.75 (s, 2H), 3.45 (s, 2H), 2.33-2.75 (m, 6H), 1.90 (t, 2H), 1.40 (m, 2H), 0.80 (m, 3H):

MS (+ve ESI): 522 (M+H)⁺,

MS (−ve ESI): 520 (M−H)⁻.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(propyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (470 mg, 0.90 mmol) yielded di-tert-butyl     2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl     phosphate (271 mg, 42% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 12.08 (br s, 1H), 10.00 (s, 1H), 9.89 (br s, 1H), 8.53 (s, 1H), 8.42 (d, 1H), 7.59 (d, 1H), 7.34 (m, 2H), 7.17 (m, 2H), 6.84 (m, 1H), 6.56 (br s, 1H), 4.25 (t, 2H), 3.94 (m, 2H), 3.76 (s, 2H), 2.79 (t, 2H), 2.71 (t, 2H), 2.50 (t, 2H), 1.93 (m, 2H), 1.48 (m, 20H), 0.89 (t, 3H):

MS (+ve ESI): 714 (M+H)⁺,

MS (−ve ESI): 712 (M−H)⁻.

EXAMPLE 42 Preparation of Compound 42 in Table 3—{(2R)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di(tert-butyl) {(2R)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl phosphate (280 mg, 0.39 mmol) yielded compound 42 in table 3 (268 mg, 100% yield) as a pale yellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 11.96 (s, 1H), 10.75 (s, 1H), 8.94 (s, 1H), 8.82 (d, 1H), 7.65 (d, 1H), 7.43 (d, 1H), 7.28-7.41 (m, 3H), 6.91 (m, 1H), 6.71 (s, 1H), 4.31 (t, 2H), 4.20 (m, 2H), 3.86 (s, 2H), 3.77 (m, 1H), 3.55-3.69 (m, 2H), 3.29 (m, 1H), 3.17 (m, 1H), 2.22-2.37 (m, 2H), 2.17 (m, 1H), 2.04 (m, 1H), 1.90 (m, 1H), 1.79 (m, 1H):

MS (+ve ESI): 600 (M+H)⁺,

MS (−ve ESI): 598 (M−H)⁻.

di(tert-butyl) {(2R)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 37a, but     starting with D-prolinol (0.87 g, 8.6 mmol) yielded     N-(3-fluorophenyl)-2-f{3-[(7-{3-[(2R)-2-(hydroxymethyl)-pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as a pale yellow solid (530 mg, 35% yield):

¹H-NMR (DMSO-d₆): 12.33 (br s, 1H), 10.38 (s, 1H), 10.20 (br s, 1H), 8.50 (s, 2H), 7.60 (d, 1H), 7.35 (m, 2H), 7.15 (s, 2H), 6.89 (dd, 1H), 6.75 (br s, 1H), 4.30 (br s, 1H), 4.16 (t, 2H), 3.73 (s, 2H), 3.39 (m, 1H), 3.19 (m, 1H), 3.08 (m, 1H), 2.98 (m, 1H), 2.17 (m, 1H), 1.95 (m, 2H), 1.80 (m, 1H), 1.49-1.73 (m, 4H):

MS (+ve ESI): 520 (M+H)⁺,

MS (−ve ESI): 518 (M−H)⁻.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(3-fluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (530 mg, 1.02 mmol) yielded di(tert-butyl)     {(2R)-1-[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl]pyrrolidin-2-yl}methyl     phosphate (280 mg, 39% yield) as a pale yellow solid:

MS (+ve ESI): 712 (M+H)⁺,

MS (−ve ESI): 710 (M−H)⁻.

EXAMPLE 43 Preparation of Compound 43 in Table 3—3-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]propyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 3-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]propyl phosphate (45 mg, 0.06 mmol) yielded compound 43 in table 3 (36 mg, 95% yield) as a pale yellow dihydrochloride salt:

¹H-NMR (DMSO d₆): 10.35 (br s, 1H), 8.78-9.10 (m, 2H), 7.55-7.62 (m, 1H), 7.42-7.50 (m, 2H), 7.28-7.40 (m, 2H), 6.80-6.87 (m, 1H), 6.65-6.79 (br m, 1H), 4.35 (t, 2H), 3.95-4.02 (m, 2H), 3.85 (s, 2H), 3.28 (t, 2H), 3.15-3.25 (m, 4H), 2.25-2.35 (m, 2H), 2.05-2.15 (m, 2H), 1.31 (t, 3H):

MS (+ve ESI): 602 (M+H)⁺.

di-tert-butyl 3-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]propyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 37a, but     starting with 3-aminopropan-1-ol (247 mg, 3.3 mmol) yielded     N-(3-fluorophenyl)-2-{3-[(7-{3-[(3-hydroxypropyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as a pale yellow solid (295 mg, 54% yield):

¹H-NMR (DMSO d₆): 10.42 (br s, 1H), 8.43-8.54 (m, 2H), 7.58-7.63 (m, 1H), 7.29-7.38 (m, 2H), 7.11-7.18 (m, 2H), 6.84-6.91 (m, 1H), 6.56-6.78 (br m, 1H), 4.18 (t, 2H), 3.72 (s, 2H), 3.45 (t, 2H), 2.67 (t, 2H), 2.58 (t, 2H), 1.84-1.95 (m, 2H), 1.51-1.61 (m, 2H):

MS (+ve ESI): 494 (M+H)⁺.

-   b) Tri(acetoxy)borohydride (750 mg, 1.48 mmol) was added to a     solution of     N-(3-fluorophenyl)-2-{3-[(7-{3-[(3-hydroxypropyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (290 mg, 0.59 mmol) and acetaldehyde (39 mg, 0.88 mmol) in     dimethylformamide (3 ml) at ambient temperature and the reaction     stirred for 2 hours. The reaction mixture was filtered, diluted with     dichloromethane (10 ml) and purified by flash chromatography on     silica gel, eluting with 3-12% methanol: dichloromethane.     Evaporation of the fractions in vacuo yielded     2-{3-[(7-{3-[ethyl(3-hydroxypropyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide     (105 mg, 34% yield) as a white solid:

¹H-NMR (DMSO dc): 10.41 (br s, 1H), 10.13-10.30 (br s, 1H), 8.43-8.55 (m, 2H), 7.57-7.65 (m, 1H), 7.28-7.39 (m, 2H), 7.09-7.21 (m, 2H), 6.83-6.92 (m, 1H), 6.65-6.81 (m, 1H), 4.15 (t, 2H), 3.73 (s, 2H), 3.41 (t, 2H), 2.41-2.58 (m, 6H under DMSO), 1.82-1.93 (m, 2H), 1.48-1.58 (m, 2H), 0.94 (t, 3H):

MS (+ve ESI): 522 (M+H)⁺.

-   c) An analogous reaction to that described in example 6c, but     starting with     2-{3-[(7-{3-[ethyl(3-hydroxypropyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide     (90 mg, 0.17 mmol) yielded di-tert-butyl     3-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]propyl     phosphate (45 mg, 37% yield) as a pale yellow solid:

MS (+ve ESI): 714 (M+H)⁺,

MS (−ve ESI): 712 (M−H)⁻.

EXAMPLE 44 Preparation of Compound 44 in Table 3—2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl](2-methoxyethyl)amino]ethyl dihydrogen phosphate

Di-tert-butyl 2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl](2-methoxyethyl)amino]ethyl phosphate (200 mg, 0.3 mmol) was solubilised in dioxane (7 ml) and treated with a mixture of dioxane/hydrochloric acid (4.0 N, 0.5 ml) at 20° C. overnight. A light yellow solid was recovered by filtration and dried in vacuo (55° C., 12 h) to yield 2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl](2-methoxyethyl)amino]ethyl dihydrogen phosphate (200 mg, 85% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆, CH₃COOD): 8.95 (s, 1H), 8.82 (d, 1H), 7.65 (d, 1H), 7.46 (d, 1H), 7.37 (m, 3H), 6.88 (m, 1H), 6.78 (s, 1H), 4.33 (m, 2H), 4.28 (m, 2H), 3.86 (s, 2H), 3.76 (m, 2H), 3.53 (m, 2H), 3.45 (m, 4H), 3.34 (s, 3H), 2.30 (m, 2H):

MS (+ve ESI): 618 (M+H)⁺.

di-tert-butyl 2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl](2-methoxyethyl)amino]ethyl phosphate used as starting material, was obtained as follows:

-   a) 2-((2-methoxyethyl)amino)ethanol (750 mg, 6.29 mmol) was added to     a solution of     2-(3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide     (960 mg, 2.11 mmol) and potassium iodide (700 mg, 4.22 mmol) in     1-methyl-2-pyrrolidinone (8 ml). The mixture was stirred at 80° C.     for 1.5 hours, cooled, added onto a silica gel column, and purified     by chromatography eluting successively with dichloromethane,     dichloromethane: methanol 96:4 to 92:8 to give     N-(3-fluorophenyl)-2-{3[(7-{3-[(2-hydroxyethyl)(2-methoxyethyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (600 mg, 53% yield) as an off white solid.

¹H-NMR (DMSO d₆, TFA): 9.0 (s, 1H), 8.83 (d, 1H), 7.65 (d, 1H), 7.48 (d, 1H), 7.36 (m, 2H), 7.28 (s, 1H), 6.88 (m, 1H), 6.80 (s, 1H), 4.32 (m, 2H), 3.86 (s, 2H), 3.80 (m, 2H), 3.73 (m, 2H), 3.48 (m, 4H), 3.37 (m, 2H), 3.34 (s, 3H), 2.28 (m, 2H)

MS (+ve ESI): 538 (M+H)⁺.

-   b) Di-tert-butyl-diethylphosphoramidite (0.56 ml, 2 mmol) was slowly     added to a mixture of     N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(2-methoxyethyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (540 mg, 1 mmol) and tetrazole (200 mg, 3 mmol) in dimethylformamide     (5 ml) at 20° C. for 2 hours. The mixture was then cooled to 0° C.     and hydrogen peroxide (9.0 N, 0.33 ml, 2.93 mmol) was slowly added     and stirring at ambient temperature was continued for 12 hours.     Sodium metabisulphite (1.14 g, 6 mmol) in solution in water (12 ml)     was then added to the reaction mixture at 0° C., which was slowly     allowed to warm to ambient temperature. The solvents were then     evaporated and the residue was purified by silica gel     chromatography, eluting with dichloromethane: methanolic ammonia     (3.0 N) 96:4 to 94:6 to yield di-tert-butyl     2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl](2-methoxyethyl)amino]ethyl     phosphate (220 mg, 30% yield):

¹H-NMR (DMSO d₆, TFA): 8.98 (s, 1H), 8.81 (d, 1H), 7.63 (d, 1H), 7.48 (d, 1H), 7.36 (m, 2H), 7.27 (s, 1H), 6.90 (t, 1H), 6.77 (s, 1H), 4.30 (m, 2H), 4.26 (m, 2H), 3.84 (s, 2H), 3.72 (m, 2H), 3.55 (m, 2H), 3.48 (m, 2H), 3.42 (m, 2H), 3.34 (s, 3H), 2.26 (m, 2H), 1.44 (s, 18H):

MS (+ve ESI): 730 (M+H)⁺.

EXAMPLE 45 Preparation of Compound 45 in Table 4—2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl](propyl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl](propyl)amino]ethyl phosphate (550 mg, 0.74 mmol) yielded compound 45 in table 4 (504 mg, 96% yield) as the dihydrochloride salt:

¹H-NMR (DMSO d₆): 11.95 (s, 1H), 10.34 (s, 1H), 8.90 (s, 1H), 8.83 (d, 1H), 7.68 (m, 1H), 7.45 (m, 2H), 7.22 (m, 2H), 6.72 (s, 1H), 4.23 (m, 4H), 3.91 (s, 2H), 3.40 (m, 2H), 3.20 (m, 2H), 3.08 (m, 2H), 1.88 (m, 4H), 1.71 (m, 2H), 0.90 (t, 3H):

MS (+ve ESI): 634 (M+H)⁺,

MS (−ve ESI): 632 (M−H)⁻.

di-tert-butyl 2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl](propyl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a) 1,4-Dihydroxybutane (33.0 ml, 366 mmol) was added over 10 minutes     to a stirred suspension of sodium hydride (14.6 g of a 60%     dispersion in oil, 366 mmol) in dimethylacetamide (200 ml) at 0° C.     and the reaction stirred for 15 minutes before being heated to     60° C. A solution of 7-fluoroquinazolin-4(3H)-one (10.0 g, 61.0     mmol) in dimethylacetamide (60 ml) was added over 5 minutes and the     reaction stirred at 110° C. for a further 5 hours. The reaction was     cooled, poured onto ice (500 g) and treated with brine (500 ml) and     5.0 N hydrochloric acid (until pH<6). The resultant solid was     collected by suction filtration, washed with water and diethyl ether     and then taken up in dimethylacetamide (100 ml). The reaction was     filtered and the filtrate evaporated in vacuo to yield     7-(4-hydroxy-butoxy)quinazolin-4(3H)-one (5.88 g, 41% yield) as a     white solid after drying in vacuo:

¹H-NMR (DMSO d₆): 8.15 (s, 1H), 8.10 (m, 1H), 7.18 (m, 2H), 4.22 (m, 2H), 3.58 (m, 2H), 1.90 (m, 2H), 1.70 (m, 2H):

MS (+ve ESI): 235 (M+H)⁺,

MS (−ve ESI): 233 (M−H)⁻.

-   b) Dimethylformamide (0.5 ml) was added to a stirred suspension of     7-(4-hydroxy-butoxy)quinazolin-4(3H)-one (4.86 g, 20.0 mmol) in     thionyl chloride (50 ml) and the reaction heated at reflux for 1     hour. The reaction was cooled, the excess thionyl chloride was     evaporated in vacuo and the residue was azeotroped with toluene     (2×50 ml) before being taken up in dimethylacetamide (50 ml).     5-amino-1H-pyrazole-3-acetic acid (2.82 g, 20 mmol) and 4.0 N     hydrochloric acid in dioxan (5.0 ml, 20 mmol) were added and the     reaction was stirred at 90° C. for 40 minutes. The reaction was     cooled to ambient temperature, poured into ice-water (500 ml) and     acidified to pH>12 with 40% aqueous sodium hydroxide solution. The     reaction was filtered, the filtrate was acidified to pH<4.8 and the     solid which precipitated was collected by suction filtration to     yield-(3-{[7-(4-chlorobutoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetic     acid (7.07 g, 91% yield) as a pale orange solid:

¹H-NMR (DMSO d₆): 12.45 (br s, 2H), 8.57 (s, 1H), 8.50 (d, 1H), 7.17 (m, 2H), 6.60 (s, 1H), 4.18 (m, 2H), 3.75 (m, 2H), 3.65 (s, 2H), 1.90 (m, 4H):

MS (+ve ESI): 376 (M+H)⁺,

MS (−ve ESI): 374 (M−H)⁻.

-   c) Phosphorus oxychloride (1.8 ml, 19.5 mmol) was added to a stirred     suspension of 2,3-difluoroaniline (2.88 g, 22.3 mmol),     (3-{[7-(4-chlorobutoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetic     acid (6.97 g, 18.6 mmol) and pyridine (100 ml) at 0° C. The reaction     was stirred for 2.5 hours at 0° C., additional phosphorus     oxychloride (0.3 ml) was added and the reaction allowed to warm to     ambient temperature over 18 hours. Ethyl acetate (200 ml) and     diethyl ether (100 ml) were added, the reaction was stirred and the     sticky solid collected by filtration before being suspended in water     (300 ml). Dilute aqueous ammonia was added until the pH was >7 and     the resultant solid was collected by suction filtration. Washing of     the resultant solid with water and then acetonitrile, followed by     prolonged drying in vacuo, yielded     2-(3-{[7-(4-chlorobutoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(2,3-difluorophenyl)acetamide     (7.6 g, 84% yield) as a pale brown solid:

¹H-NMR (DMSO d₆): 10.20 (s, 1H), 8.63 (s, 1H), 8.58 (d, 1H), 7.69 (m, 1H), 7.23 (m, 1H), 7.15 (m, 3H), 6.68 (s, 1H), 4.14 (m, 2H), 3.81 (s, 2H), 3.70 (m, 2H), 1.88 (m, 4H):

MS (+ve ESI): 487 (M+H)+

MS (−ve ESI): 485 (M−H)⁻.

-   d) An analogous reaction to that described in example 28f, but     starting with 2-(propylamino)ethanol (765 mg, 7.40 mmol) and     2-(3-{[7-(4-chlorobutoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(2,3-difluorophenyl)acetamide     (1.20 g, 2.47 mmol) yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{4-[propyl(2-hydroxyethyl)amino]butoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as a brown solid (625 mg, 46% yield):

¹H-NMR (DMSO d₆): 10.3 (br s, 1H), 8.49 (s, 1H), 8.45 (m, 1H), 7.70 (m, 1H), 7.15 (m, 3H), 7.1 (s, 1H), 6.58 (br, s, 1H), 4.1 (m, 2H), 3.80 (s, 2H), 3.42 (m, 2H), 2.45 (m, 4H), 2.33 (m, 2H), 1.77 (m, 2H), 1.55 (m, 2H), 1.35 (m, 2H), 0.81 (t, 3H):

MS (+ve ESI): 554 (M+H)+

MS (−ve ESI): 552 (M−H)⁻.

-   e) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{4-[(2-hydroxyethyl)(propyl)amino]butoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (540 mg, 0.98 mmol) yielded di-tert-butyl     2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl](propyl)amino]ethyl     phosphate (566 mg, 78% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 12.3 (s, 1H), 10.18 (m, 2H), 8.51 (m, 2H), 7.72 (m, 1H), 7.15 (m, 4H), 6.77 (s, 1H), 4.15 (m, 2H), 3.85 (m, 4H), 2.65 (m, 2H), 2.40 (m, 2H), 1.78 (m, 2H), 1.56 (m, 2H), 1.4 (m, 2H), 1.39 (s, 18H), 0.85 (t, 3H):

MS (+ve ESI): 746 (M+H)+

MS (−ve ESI): 744 (M−H)⁻.

EXAMPLE 46 Preparation of Compound 46 in Table 4—2-[[4-({4-[5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl](ethyl)amino]ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di(tert-butyl) 2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl](ethyl)amino]ethyl phosphate (386 mg, 0.53 mmol) yielded compound 46 in table 4 (340 mg, 93% yield) as a white dihydrochloride salt:

¹H-NMR (DMSO d₆): 11.97 (s, 1H), 10.35 (s, 1H), 8.92 (s, 1H), 8.85 (d, 1H), 7.67 (m, 1H), 7.45 (m, 2H), 7.18 (m, 2H), 6.75 (s, 1H), 4.23 (m, 4H), 3.90 (s, 2H), 3.39 (m, 2H), 3.20 (m, 4H), 1.87 (m, 4H), 1.25 (t, 3H):

MS (+ve ESI): 619 (M+H)+

MS (−ve ESI): 617 (M−H)⁻.

di(tert-butyl) 2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl](ethyl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 45d, but     starting with 2-(ethylamino)ethanol (468 mg, 5.25 mmol) yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{4-[ethyl(2-hydroxyethyl)amino]butoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as an off-white solid (443 mg, 47% yield):

¹H-NMR (DMSO d₆): 10.25 (br s, 1H), 8.45 (m, 2H), 7.70 (m, 1H), 7.12 (m, 4H), 6.58 (br s, 1H), 4.25 (br s, 1H), 4.13 (m, 2H), 3.80 (s, 2H), 3.42 (m, 2H), 1.76 (m, 2H), 1.55 (m, 2H), 0.95 (t, 3H):

MS (+ve ESI): 540 (M+H)⁺

MS (−ve ESI): 538 (M−H)⁻.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{4-[ethyl(2-hydroxyethyl)amino]butoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (385 mg, 0.71 mmol) yielded di(tert-butyl)     2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl](ethyl)amino]ethyl     phosphate (393 mg, 75% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 12.30 (s, 1H), 10.18 (br s, 1H), 8.50 (m, 2H), 7.71 (m, 1H), 7.15 (m, 4H), 6.78 (s, 1H), 4.3 (m, 2H), 3.85 (m, 4H), 2.68 (m, 2H), 1.78 (m, 2H), 1.58 (m, 2H), 1.40 (s, 18H), 0.97 (t, 3H):

MS (+ve ESI): 732 (M+H)⁺

MS (−ve ESI): 730 (M−H)⁻.

EXAMPLE 47 Preparation of Compound 47 in Table 4—{(2R)-1-[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl]pyrrolidin-2-yl}methyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di(tert-butyl) {(2R)-1-[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl]pyrrolidin-2-yl}methyl phosphate (464 mg, 0.62 mmol) yielded compound 47 in table 4 (400 mg, 91% yield) as an off-white dihydrochloride salt:

¹H-NMR (DMSO d₆): 11.95 (s, 1H), 10.35 (s, 1H), 8.92 (s, 1H), 8.83 (d, 1H), 7.68 (m, 1H), 7.45 (m, 2H), 7.18 (m, 2H), 6.71 (s, 1H), 4.2 (m, 4H), 3.92 (s, 2H), 3.72 (m, 1H), 3.60 (m, 1H), 3.45 (m, 1H), 3.15 (m, 2H), 2.15 (m, 1H), 1.7-2.1 (m, 7H):

MS (+ve ESI): 631 (M+H)⁺

MS (−ve ESI): 630 (M−H)⁻.

di(tert-butyl) {(2R)-1-[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl]pyrrolidin-2-yl}methyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 45d, but     starting with D-prolinol (530 mg, 5.25 mmol) yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{4-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]butoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as an off-white solid (516 mg, 54% yield):

¹H-NMR (DMSO d₆): 10.25 (br s, 1H), 8.45 (m, 2H), 7.7 (m, 1H), 7.15 (m, 4H), 6.6 (br s, 1H), 4.30 (br s, 1H), 4.21 (m, 2H), 3.80 (s, 2H), 3.40 (m, 1H), 3.20 (m, 1H), 3.05 (m, 1H), 2.85 (m, 1H), 2.40 (m, 1H), 2.30 (m, 1H), 2.10 (m, 1H), 1.77 (m, 3H), 1.6 (m, 5H):

MS (+ve ESI): 552 (M+H)⁺.

MS (−ve ESI): 550 (M−H)⁻.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{4-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]butoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (450 mg, 0.82 mmol) yielded di(tert-butyl)     {(2R)-1-[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl]pyrrolidin-2-yl}methyl     phosphate (470 mg, 77% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 12.3 (s, 1H), 10.18 (s, 1H), 8.50 (m, 2H), 7.71 (m, 1H), 7.18 (m, 4H), 6.77 (s, 1H), 4.15 (m, 2H), 3.80 (m, 3H), 3.62 (m, 1H), 3.05 (m, 1H), 2.80 (m, 1H), 2.65 (m, 1H), 2.37 (m, 1H), 2.18 (m, 1H), 1.80 (m, 3H), 1.62 (m, 5H), 1.38 (s, 18H):

MS (+ve ESI): 744 (M+H)⁺.

MS (−ve ESI): 742 (M−H)⁻.

EXAMPLE 48 Preparation of Compound 48 in Table 4—2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)butyl](methyl)amino]ethyl dihydrogen-phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)butyl](methyl)amino]ethyl phosphate (250 mg, 0.35 mmol) yielded compound 48 in table 4 (263 mg, 100% yield) as an off-white dihydrochloride salt:

¹H-NMR (DMSO d₆): 11.95 (s, 1H), 10.35 (s, 1H), 8.92 (s, 1H), 8.83 (d, 1H), 7.69 (m, 1H), 7.45 (m, 2H), 7.29 (m, 2H), 6.75 (s, 1H), 4.22 (m, 4H), 3.81 (s, 2H), 3.39 (m, 2H), 3.20 (m, 2H), 2.80 (s, 3H), 1.85 (m, 4H):

MS (+ve ESI): 605 (M+H)⁺

MS (−ve ESI): 603 (M−H)⁻.

di-tert-butyl 2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)butyl](methyl)amino]ethyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 45d, but     starting with 2-(methylamino)ethanol (394 mg, 5.25 mmol)     yielded)-(2,3-difluorophenyl)-2-{3-[(7-{4-[(2-hydroxyethyl)(methyl)amino]butoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as an off-white solid (536 mg, 58% yield):

¹H-NMR (DMSO d₆): 10.25 (br s, 1H), 8.45 (m, 2H), 7.71 (m, 1H), 7.15 (m, 4H), 6.58 (br s, 1H), 4.3 (br s, 1H), 4.12 (m, 2H), 3.80 (s, 2H), 3.45 (m, 2H), 2.39 (m, 4H), 2.15 (s, 3H), 1.79 (m, 2H), 1.58 (m, 2H):

MS (+ve ESI): 526 (M+H)⁺

MS (−ve ESI): 524 (M−H)⁻.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{4-[(2-hydroxyethyl)(methyl)amino]butoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (460 mg, 0.88 mmol) yielded di-tert-butyl     2-[[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)butyl](methyl)amino]ethyl     phosphate (368 mg, 59% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 12.30 (s, 1H), 10.17 (m, 2H), 8.50 (m, 2H), 7.70 (m, 1H), 7.18 (m, 4H), 6.77 (s, 1H), 4.15 (m, 2H), 3.9 (m, 2H), 3.85 (s, 2H), 2.60 (m, 2H), 2.43 (m, 2H), 2.20 (s, 3H), 1.8 (m, 2H), 1.58 (m, 2H), 1.40 (s, 18H):

MS (+ve ESI): 718 (M+H)⁺

MS (−ve ESI): 716 (M−H)⁻.

EXAMPLE 49 Preparation of Compound 49 in Table 4—{(2S)-1-[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl]pyrrolidin-2-yl}methyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di(tert-butyl) {(2S)-1-[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl]pyrrolidin-2-yl}methyl phosphate (386 mg, 0.53 mmol) yielded compound 49 in table 4 (340 mg, 93% yield) as an off-white dihydrochloride salt:

¹H-NMR (DMSO d₆): 11.7 (br s, 1H), 10.30 (s, 1H), 8.87 (s, 1H), 8.75 (d, 1H), 7.68 (m, 1H), 7.40 (m, 2H), 7.19 (m, 2H), 6.71 (s, 1H), 4.20 (m, 2H), 4.18 (m, 2H), 3.90 (s, 2H), 3.7 (m, 1H), 3.58 (m, 1H), 3.42 (m, 1H), 3.1 (m, 2H), 2.15 (m, 1H), 1.75-2.1 (m, 7H):

MS (+ve ESI): 630 (M+H)⁺

MS (−ve ESI): 632 (M−H)⁻.

di(tert-butyl) {(2S)-1-[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl]pyrrolidin-2-yl}methyl phosphate used as starting material was obtained as follows:

-   a) An analogous reaction to that described in example 45d, but     starting with L-prolinol (530 mg, 5.25 mmol) yielded     N-(2,3-difluorophenyl)-2-{3-[(7-{4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]butoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     as an off-white solid (550 mg, 57% yield):

¹H-NMR (DMSO d₆): 12.38 (br s, 1H), 10.20 (br s, 1H), 8.47 (m, 2H), 7.70 (m, 1H), 7.15 (m, 4H), 6.62 (br s, 1H), 4.28 (br s, 1H), 4.15 (m, 2H), 3.81 (s, 2H), 3.40 (m, 1H), 3.20 (m, 1H), 3.02 (m, 1H), 2.81 (m, 1H), 2.38 (m, 1H), 2.30 (m, 1H), 2.10 (m, 1E1), 1.78 (m, 3H), 1.58 (m, 5H):

MS (+ve ESI): 552 (M+H)⁺

MS (−ve ESI): 550 (M−H)⁻.

-   b) An analogous reaction to that described in example 6c, but     starting with     N-(2,3-difluorophenyl)-2-{3-[(7-{4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]butoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetamide     (340 mg, 0.62 mmol) yielded di(tert-butyl)     {(2S)-1-[4-({4-[(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)butyl]pyrrolidin-2-yl}methyl     phosphate (328 mg, 71% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 12.30 (br s, 1H), 10.15 (s, 2H), 8.48 (m, 2H), 7.68 (m, 1H), 7.15 (m, 4H), 6.75 (br s, 1H), 4.12 (m, 2H), 3.80 (m, 2H), 3.61 (m, 1H), 3.05 (m, 1H), 2.80 (m, 1H), 2.62 (m, 1H), 2.35 (m, 1H), 2.15 (m, 1H), 1.81 (m, 3H), 1.60 (m, 5H), 1.38 (s, 18H):

MS (+ve ESI): 744 (M+H)⁺

MS (−ve ESI): 742 (M−H)⁻.

EXAMPLE 50 Preparation of Compound 50 in Table 5—2-{ethyl[3-({6-fluoro-4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl]oxy)propyl]amino}ethyl dihydrogen phosphate

An analogous reaction to that described in example 1, but starting with di-tert-butyl 2-{ethyl[3-({6-fluoro-4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}ethyl phosphate (275 mg, 0.38 mmol) yielded compound 50 in table 5 (260 mg, 100% yield) as an off-white dihydrochloride salt:

¹H-NMR (DMSO d₆): 12.0 (br s, 1H), 10.87 (s, 1H), 8.96 (s, 1H), 8.87 (d, 1H), 7.65 (m, 2H), 7.38 (m, 2H), 6.89 (m, 2H), 6.77 (s, 1H), 4.42 (t, 2H), 4.26 (m, 2H), 3.86 (s, 2H), 3.44 (t, 2H), 3.35 (m, 2H), 3.28 (m, 2H), 2.33 (m, 2H), 1.31 (t, 3H):

MS (+ve ESI): 606 (M+H)⁺.

di-tert-butyl 2-{ethyl[3-({6-fluoro-4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}ethyl phosphate phosphate used as starting material was obtained as follows:

-   a) Benzyl alcohol (4.27 g, 39.5 mmol) was added dropwise to a     stirred suspension of sodium hydride (1.6 g of a 60% dispersion in     mineral oil, 40.0 mmol) in dimethylformamide (50 ml) at 0° C. The     reaction was stirred at 0° C. for 1 hour before addition of     6,7-difluoroquinazolin-4(1H)-one (3.60 g, 19.8 mmol) whereupon the     reaction was heated to 60° C. for 2 hours. The reaction was cooled     to ambient temperature, poured into water (200 ml) and the resultant     solid collected by suction filtration. Drying of the solid in vacuo     yielded 7-(benzyloxy)-6-fluoroquinazolin-4(1H)-one (4.45 g, 83%     yield) as a pale brown solid:

¹H-NMR (DMSO d₆): 12.24 (br s, 1H), 8.05 (s, 1H), 7.80 (d, 1H), 7.52 (m, 2H), 7.44 (m, 3H), 7.38 (t, 1H), 5.35 (s, 2H).

-   b) 7-(Benzyloxy)-6-fluoroquinazolin-4(1H)-one (2.00 g, 7.41 mmol)     was taken up in phosphorus oxychloride (20 ml) and the reaction     heated at reflux for 90 minutes. The reaction was cooled, azeotroped     with toluene (2×50 ml) and taken up in dichloromethane (5 ml) The     organic phase was washed with saturated aqueous sodium hydrogen     carbonate solution and thend ried over magnesium sulphate. Solvent     evaporation in vacuo followed by drying of the solid in vacuo     yielded 7-(benzyloxy)-4-chloro-6-fluoroquinazoline (1.50 g, 71%     yield) as a pale yellow solid:

¹H-NMR (CDCl₃): 8.93 (s, 1H), 7.89 (d, 1H), 7.51 (m, 3H), 7.35-7.46 (m, 3H), 5.32 (s, 2H).

-   c) A mixture of 7-(benzyloxy)-4-chloro-6-fluoroquinazoline (1.20 g,     4.16 mmol) and     2-(3-amino-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide (0.97 g,     4.15 mmol) were heated at reflux in 2-propanol (20 ml) for 2 hours.     The reaction was cooled to ambient temperature, diluted with diethyl     ether and the resultant solid collected by suction filtration.     Prolonged drying in vacuo yielded     2-(3-{[7-(benzyloxy)-6-fluoroquinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide     (2/.00 g, 92% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 11.72 (br s, 1H), 10.71 (s, 1H), 8.90 (s, 1H), 8.82 (d, 1H), 7.65 (m, 2H), 7.55 (m, 2H), 7.32-7.50 (m, 5H), 6.89 (m, 1H), 6.76 (s, 1H), 5.42 (s, 2H), 3.84 (s, 2H):

MS (+ve ESI): 487 (M+H)⁺.

-   d) A solution of     2-(3-{[7-(benzyloxy)-6-fluoroquinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide     (hydrochloride salt) (1.95 g, 3.74 mmol) in trifluoroacetic acid     (20 ml) was heated at reflux for 7 hours. The reaction was cooled to     ambient temperature, and the trifluoroacetic acid removed in vacuo.     Trituration of the residue with diethyl ether (2×25 ml) yielded     2-{3-[(6-fluoro-7-hydroxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide     (2.00 g, 100% yield) as a pale yellow solid:

MS (+ve ESI): 397 (M+H)⁺.

-   e) Caesium carbonate (2.67 g, 8.2 mmol) was added to a stirred     solution of     2-{3-[(6-fluoro-7-hydroxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide     (2.09 g, 4.10 mmol) and 3-bromo-1-chloropropane (0.44 ml, 4.5 mmol)     in dimethylformamide (20 ml) and the reaction heated at 70° C. for 1     hour. The reaction was cooled to ambient temperature, poured into     water (150 ml) and the resultant solid was collected by suction     filtration. Purification by flash chromatography on silica gel,     eluting with 3-8% methanol: dichloromethane gave     2-(3-{[7-(3-chloropropoxy)-6-fluoroquinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide     (1.10 g, 57% yield) as a pale yellow solid, following solvent     evaporation in vacuo:

MS (+ve ESI): 473 (M+H)⁺.

-   f) An analogous reaction to that described in example 45d, but     starting with 2-(ethylamino)ethanol (282 mg, 3.17 mmol) and     2-(3-{[7-(3-chloropropoxy)-6-fluoroquinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide     (500 mg, 1.06 mmol) yielded     2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6-fluoroquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide     (408 mg, 73% yield) as an off-white solid:

¹H-NMR (DMSO d₆): 12.40 (s, 1H), 10.40 (s, 1H), 10.15 (s, 1H), 8.53 (s, 1H), 8.50 (br s, 1H), 7.62 (d, 1H), 7.35 (m, 3H), 6.89 (m, 1H), 6.78 (br s, 1H), 4.28 (m, 3H), 3.75 (br s, 2H), 3.45 (m, 2H), 2.62 (t, 2H), 2.50 (m, 4H under DMSO), 1.91 (m, 2H), 0.98 (t, 3H):

MS (+ve ESI): 526 (M+H)⁺.

-   g) An analogous reaction to that described in example 6c, but     starting with     2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6-fluoroquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide     (266 mg, 0.51 mmol) yielded di-tert-butyl     2-{ethyl[3-({6-fluoro-4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]quinazolin-7-yl}oxy)propyl]amino}ethyl     phosphate (288 mg, 79% yield) as a pale yellow solid:

¹H-NMR (CDCl₃): 12.70 (br s, 1H), 9.90 (br s, 1H), 9.40 (s, 1H), 8.60 (s, 1H), 7.98 (d, 1H), 7.56 (d, 1H), 7.15-7.30 (m, 3H), 6.76 (m, 1H), 6.24 (br s, 1H), 4.14 (t, 2H), 4.03 (q, 2H), 3.83 (s, 2H), 2.79 (t, 2H), 2.70 (t, 2H), 2.61 (m, 2H), 1.95 (m, 2H), 1.48 (s, 18H), 1.05 (t, 3H):

MS (+ve ESI: 718 (M+H)⁺.

2-(3-amino-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide used in step 50c was prepared as follows:

-   h) Pentafluorophenyl trifluoroacetate (11.9 g, 42.5 mmol) was added     dropwise to a solution of (3-amino-1H-pyrazol-5-yl)acetic acid (3.00     g, 21.3 mmol) and pyridine (3.80 ml, 46.7 mmol) in dimethylformamide     (25 ml) at 0° C. The reaction was allowed to warm to ambient     temperature over 90 minutes before addition of 3-fluoroaniline (4.10     ml, 42.5 mml). The reaction was stirred for 2.5 hours at ambient     temperature and then poured into 0.2 N hydrochloric acid and     extracted with dichloromethane (3×50 ml). Addition of excess diethyl     ether caused precipitation of     2,2,2-trifluoro-N-(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)acetamide     (2.08 g, 30% yield) which was isolated as a pale orange solid:

MS (+ve ESI): 331 (M+H)⁺.

-   i) A solution of     2,2,2-trifluoro-N-(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)acetamide     (3.10 g, 9.4 mmol) in methanol (25 ml) and 2.0N aqueous hydrochloric     acid (20 ml, 40 mml) was heated at 50° C. for 2.5 hours. The     reaction was cooled to ambient temperature, basified with solid     sodium hydrogen carbonate and then concentrated in vacuo until a     solid began to precipitate. Collection of the resultant solid by     suction filtration followed by prolonged drying in vacuo yielded     2-(3-amino-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide (1.05 g, 48%     yield) as a pale brown solid:

¹H-NMR (DMSO d₆): 11.25 (br s, 1H), 10.30 (br s 1H), 7.60 (d, 1H), 7.32 (m, 2H), 6.86 (m, 1H), 5.31 (s, 1H), 4.62 (br s, 2H), 3.48 (s, 2H). 

1. A compound, which is 2-[[3-({4-[(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-3-yl)amino]-quinazolin-7-yl}oxy)propyl](ethyl)amino]ethyl dihydrogen phosphate, or a pharmaceutically acceptable salt thereof.
 2. A pharmaceutical composition comprising a compound according to claim 1 in association with a pharmaceutically acceptable diluent or carrier. 